Novel compounds

ABSTRACT

Novel substituted 1,5,7-trisubstituted-1,8-napthyridin-2(1H)-one compounds; 1,5,7 trisubstituted-1,6-napthyridine-2-(1H)-one compounds and 1,5,7-trisubstituted quinoline-2(1H)-one compounds, processes for the preparation thereof, the use thereof in treating CSBP/p38 kinase mediated diseases and pharmaceutical compositions for use in such therapy.

FIELD OF THE INVENTION

This invention relates to a novel group of1,5,7-trisubstituted-1,8-napthyridin-2(1H)-one compounds; 1,5,7trisubstituted-1,6-napthyridine-2-(1H)-one compounds and1,5,7-trisubstituted quinoline-2(1H)-one compounds, processes for thepreparation thereof, the use thereof in treating CSBP/p38 kinasemediated diseases and pharmaceutical compositions for use in suchtherapy.

BACKGROUND OF THE INVENTION

Intracellular signal transduction is the means by which cells respond toextracellular stimuli. Regardless of the nature of the cell surfacereceptor (e.g. protein tyrosine kinase or seven-transmembrane G-proteincoupled), protein kinases and phosphatases along with phopholipases arethe essential machinery by which the signal is further transmittedwithin the cell [Marshall, J. C. Cell, 80, 179-278 (1995)]. Proteinkinases can be categorized into five classes with the two major classesbeing, tyrosine kinases and serine/threonine kinases depending uponwhether the enzyme phosphorylates its substrate(s) on specifictyrosine(s) or serine/threonine(s) residues [Hunter, T., Methods inEnzymology (Protein Kinase Classification) p. 3, Hunter, T.; Sefton, B.M.; eds. vol. 200, Academic Press; San Diego, 1991].

For most biological responses, multiple intracellular kinases areinvolved and an individual kinase can be involved in more than onesignaling event. These kinases are often cytosolic and can translocateto the nucleus or the ribosomes where they can affect transcriptionaland translational events, respectively. The involvement of kinases intranscriptional control is presently much better understood than theireffect on translation as illustrated by the studies on growth factorinduced signal transduction involving MAP/ERK kinase [Marshall, C. J.Cell, 80, 179 (1995); Herskowitz, I. Cell. 80, 187 (1995); Hunter, T.Cell, 80, 225 (1995); Seger, R., and Krebs, E. G. FASEB J., 726-735(1995)].

While many signaling pathways are part of cell homeostasis, numerouscytokines (e.g., IL-1 and TNF) and certain other mediators ofinflammation (e.g., COX-2, and iNOS) are produced only as a response tostress signals such as bacterial lipopolysaccharide (LPS). The firstindications suggesting that the signal transduction pathway leading toLPS-induced cytokine biosynthesis involved protein kinases came fromstudies of Weinstein [Weinstein, et al., J. Immunol. 151, 3829 (1993)]but the specific protein kinases involved were not identified. Workingfrom a similar perspective, Han [Han, et al., Science 265, 808 (1994)]identified murine p38 as a kinase which is tyrosine phosphorylated inresponse to LPS. Definitive proof of the involvement of the p38 kinasein LPS-stimulated signal transduction pathway leading to the initiationof proinflammatory cytokine biosynthesis was provided by the independentdiscovery of p38 kinase by Lee [Lee; et al., Nature, 372, 739 (1994)] asthe molecular target for a novel class of anti-inflammatory agents. Thediscovery of p38 (termed by Lee as CSBP 1 and 2) provided a mechanism ofaction of a class of anti-inflammatory compounds for which SK&F 86002was the prototypic example. These compounds inhibited IL-1 and TNFsynthesis in human monocytes at concentrations in the low uM range [Lee,et al., Int. J. Immunopharmac. 10(7), 835 (1988)] and exhibited activityin animal models which are refractory to cyclooxygenase inhibitors [Lee;et al., Annals N.Y. Acad. Sci., 696, 149 (1993)].

It is now firmly established that CSBP/p38 is a one of several kinasesinvolved in a stress-response signal transduction pathway, which isparallel to and largely independent of the analogous mitogen-activatedprotein kinase (MAP) kinase cascade. Stress signals, including LPS,pro-inflammatory cytokines, oxidants, UV light and osmotic stress,activate kinases upstream from CSBP/p38 which in turn phosphorylateCSBP/p38 at threonine 180 and tyrosine 182 resulting in CSBP/p38activation. MAPKAP kinase-2 and MAPKAP kinase-3 have been identified asdownstream substrates of CSBP/p38 which in turn phosphorylate heat shockprotein Hsp 27 (FIG. 1). Additional downstream substrates known to bephosphorylated by p38 include kinases (Mnk1/2, MSK1/2 and PRAK) andtranscription factors (CHOP, MEF2, ATF2 and CREB). While many of thesignaling pathways required for cytokine biosynthesis remain unknown itappears clear that many of the substrates for p38 listed above areinvolved. [Cohen, P. Trends Cell Biol., 353-361 (1997) and Lee, J. C. etal, Pharmacol. Ther. vol. 82, nos. 2-3, pp. 389-397, 1999].

What is known, however, is that in addition to inhibiting IL-1 and TNF,CSBP/p38 kinase inhibitors (SK&F 86002 and SB 203580) also decrease thesynthesis of a wide variety of pro-inflammatory proteins including,IL-6, IL-8, GM-CSF and COX-2. Inhibitors of CSBP/p38 kinase have alsobeen shown to suppress the TNF-induced expression of VCAM-1 onendothelial cells, the TNF-induced phosphorylation and activation ofcytosolic PLA2 and the IL-1-stimulated synthesis of collagenase andstromelysin. These and additional data demonstrate that CSBP/p38 isinvolved not only cytokine synthesis, but also in cytokine signaling[CSBP/P38 kinase reviewed in Cohen, P. Trends Cell Biol., 353-361(1997)].

Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) are biologicalsubstances produced by a variety of cells, such as monocytes ormacrophages. IL-1 has been demonstrated to mediate a variety ofbiological activities thought to be important in immunoregulation andother physiological conditions such as inflammation [See, e.g.,Dinarello et al., Rev. Infect. Disease, 6, 51 (1984)]. The myriad ofknown biological activities of IL-1 include the activation of T helpercells, induction of fever, stimulation of prostaglandin or collagenaseproduction, neutrophil chemotaxis, induction of acute phase proteins andthe suppression of plasma iron levels.

There are many disease states in which excessive or unregulated IL-1production is implicated in exacerbating and/or causing the disease.These include rheumatoid arthritis, osteoarthritis, endotoxemia and/ortoxic shock syndrome, other acute or chronic inflammatory disease statessuch as the inflammatory reaction induced by endotoxin or inflammatorybowel disease; tuberculosis, atherosclerosis, muscle degeneration,cachexia, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis,gout, traumatic arthritis, rubella arthritis, and acute synovitis.Evidence also links IL-1 activity to diabetes and pancreatic β cells[review of the biological activities which have been attributed to IL-1Dinarello, J. Clinical Immunology, 5 (5), 287-297 (1985)].

Excessive or unregulated TNF production has been implicated in mediatingor exacerbating a number of diseases including rheumatoid arthritis,rheumatoid spondylitis, osteoarthritis, gouty arthritis and otherarthritic conditions; sepsis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, adult respiratory distresssyndrome, cerebral malaria, chronic pulmonary inflammatory disease,silicosis, pulmonary sarcososis, bone resorption diseases, reperfusioninjury, graft vs. host reaction, allograft rejections, fever andmyalgias due to infection, such as influenza, cachexia secondary toinfection or malignancy, cachexia, secondary to acquired immunedeficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloidformation, scar tissue formation, Crohn's disease, ulcerative colitis,or pyresis.

Interleukin-8 (IL-8) is a chemotactic factor produced by several celltypes including mononuclear cells, fibroblasts, endothelial cells, andkeratinocytes. Its production from endothelial cells is induced by IL-1,TNF, or lipopolysachharide (LPS). IL-8 stimulates a number of functionsin vitro. It has been shown to have chemoattractant properties forneutrophils, T-lymphocytes, and basophils. In addition it induceshistamine release from basophils from both normal and atopic individualsas well as lysozomal enzyme release and respiratory burst fromneutrophils. IL-8 has also been shown to increase the surface expressionof Mac-1 (CD11b/CD18) on neutrophils without de novo protein synthesis,this may contribute to increased adhesion of the neutrophils to vascularendothelial cells. Many diseases are characterized by massive neutrophilinfiltration. Conditions associated with an increased in IL-8 production(which is responsible for chemotaxis of neutrophil into the inflammatorysite) would benefit by compounds which are suppressive of IL-8production.

IL-1 and TNF affect a wide variety of cells and tissues and thesecytokines as well as other leukocyte derived cytokines are important andcritical inflammatory mediators of a wide variety of disease states andconditions. The inhibition of these cytokines is of benefit incontrolling, reducing and alleviating many of these disease states.

In addition to the involvement of CSBP/p38 signaling in the productionof IL-1, TNF, IL-8, IL-6, GM-CSF, COX-2, collagenase and stromelysin,signal transduction via CSBP/p38 is required for the action of severalof these same pro-inflammatory proteins plus many others (VEGF, PDGF,NGF) [Ono, K. and Han, J. Cellular Signalling, 12 1-13 (2000)]. Theinvolvement of CSBP/p38 in multiple stress-induced signal transductionpathways provides additional rationale for the potential utility ofCSBP/p38 in the treatment of diseases resulting from the excessive anddestructive activation of the immune system. This expectation issupported by the potent and diverse activities described for CSBP/p38kinase inhibitors [Badger, et al., J. Pharm. Exp. Thera. 279 (3):1453-1461. (1996); Griswold, et al, Pharmacol. Comm. 7, 323-229 (1996);Jackson, et al., J. Pharmacol. Exp. Ther. 284, 687-692 (1998);Underwood, et al., J. Pharmacol. Exp. Ther. 293, 281-288 (2000); Badger,et al., Arthritis Rheum. 43,175-183 (2000)].

There remains a need for treatment, in this field, for compounds whichare cytokine suppressive anti-inflammatory drugs, i.e. compounds whichare capable of inhibiting the CSBP/p38/RK kinase.

Other containing pharmacophores having varying pharmaceutical,insecticidal, and herbicidal activity may be found in the art, such asin WO 98/33798; WO 98/23613; WO 95/19774, now U.S. Pat. No. 6,265,410;WO 00/23444; WO 01/19828; U.S. Pat. No. 5,532,370; U.S. Pat. No.5,597,776; JP 2000-38350; WO 00/43374; WO 98/08846; WO 01/55147, WO01/64679, WO 01/38312, WO 01/37837 and WO 02/059083.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 demonstrates the p38 kinase cascade.

SUMMARY OF THE INVENTION

This invention relates to the novel compounds of Formula (I) and (Ia),and pharmaceutical compositions comprising a compound of Formula (I) and(Ia), and a pharmaceutically acceptable diluent or carrier.

This invention relates to a method of treating a CSBP/RK/p38 kinasemediated disease in a mammal in need thereof, which comprisesadministering to said mammal an effective amount of a compound ofFormula (I) and (Ia).

This invention also relates to a method of inhibiting cytokines and thetreatment of a cytokine mediated disease, in a mammal in need thereof,which comprises administering to said mammal an effective amount of acompound of Formula (I) and (Ia).

This invention more specifically relates to a method of inhibiting theproduction of IL-1 in a mammal in need thereof which comprisesadministering to said mammal an effective amount of a compound ofFormula (I) and (Ia).

This invention more specifically relates to a method of inhibiting theproduction of IL-6 in a mammal in need thereof which comprisesadministering to said mammal an effective amount of a compound ofFormula (I) and (Ia).

This invention more specifically relates to a method of inhibiting theproduction of IL-8 in a mammal in need thereof which comprisesadministering to said mammal an effective amount of a compound ofFormula (I) and (Ia).

This invention more specifically relates to a method of inhibiting theproduction of TNF in a mammal in need thereof which comprisesadministering to said mammal an effective amount of a compound ofFormula (I) and (Ia).

Accordingly, the present invention provides a compound of Formula (I)and (Ia):

wherein

-   R₁ is an optionally substituted aryl or an optionally substituted    heteroaryl ring;-   X is halogen, R₂, OR₂, S(O)_(m)R₂, (CH₂)_(n)N(R₁₀)S(O)_(m)R₂,    (CH₂)_(n)N(R₁₀)C(O)R₂, (CH₂)_(n)NR₄R₁₄, NR₂(CH₂)_(n)NR₄R₁₄,    O(CH₂)_(n)NR₄R₁₄, S(CH₂)_(n)NR₄R₁₄, (CH₂)_(n)J, NR₂(CH₂)_(n)J,    O(CH₂)_(n)J, S(CH₂)_(n)J, or (CH₂)_(n)N(R₂)₂;-   J is an optionally substituted heteroaryl ring;-   n is 0 or an integer having a value of 1 to 10;-   m is 0 or an integer having a value of 1 or 2;-   q is 0 or an integer having a value of 1 to 10;-   R₂ is hydrogen, C₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,    heteroarylC₁₋₁₀ alkyl, which moieties are all optionally    substituted, or R₂ is the moiety X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or    C(A₁)(A₂)(A₃);-   X₁ is N(R₁₀), O, S(O)_(m), or CR₁₀R₂₀;-   X₂ is independently hydrogen, halogen or C₁₋₄ alkyl;-   A₁ is, an optionally substituted C₁₋₁₀ alkyl;-   A₂ is an optionally substituted C₁₋₁₀ alkyl;-   A₃ is hydrogen or is an optionally substituted C₁₋₁₀ alkyl;-   G₁ and G₂ are independently selected from is N, or C—X₂, provided    that G₁ and G₂ are not both nitrogen;-   R₃ is a hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylC₁₋₄alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,    heteroarylC₁₋₁₀ alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl    moiety, which moieties are optionally substituted; provided that R₃    is not hydrogen or methyl when G₁ is nitrogen, G₂ is C—X₂, X₂ is    hydrogen, R₁ is an optionally substituted phenyl, X is R₂ and R₂ is    hydrogen;-   R₄ and R₁₄ are each independently selected from hydrogen, optionally    substituted C₁₋₄ alkyl, optionally substituted aryl, or optionally    substituted aryl-C₁₋₄ alkyl, arylC₁₋₁₀ alkyl, heteroaryl or    heteroarylC₁₋₁₀ alkyl, wherein each of these moieties may be    optionally substituted;-   R₁₀ and R₂₀ are independently selected from hydrogen or C₁₋₄alkyl;    or    a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to novel compounds of Formula (I) and(Ia), or a pharmaceutically acceptable salt thereof.

Suitably, for compounds of Formula (I), and (Ia), R₁ is an aryl, orheteroaryl ring, which ring is optionally substituted. The R₁ aryl orheteroaryl rings may be substituted one or more times, preferably 1 to 4times, independently, by substituents selected from halogen, C₁₋₄ alkyl,halo-substituted-C₁₋₄ alkyl, cyano, nitro, (CR₁₀R₂₀)_(v)NR₄R₁₄,(CR₁₀R₂₀)_(v)C(Z)NR₄R₁₄, (CR₁₀R₂₀)_(v)C(Z)OR₈, (CR₁₀R₂₀)_(v)COR_(a′),(CR₁₀R₂₀)_(v)C(O)H, SR₅, S(O)R₅, S(O)₂R₅, (CR₁₀R₂₀)_(v)OR₈, ZC(Z)R₁₁,NR₁₀C(Z)R₁₁, or NR₁₀S(O)₂R₇.

Suitably, when R₁ is an aryl moiety, such as a phenyl ring, the ring isoptionally substituted one or more times by halogen, C₁₋₄ alkyl, orhalo-substituted-C₁₋₄ alkyl. In one embodiment the phenyl ring issubstituted in the 2, 4, or 6-position, or di-substituted in the2,4-position, such as 2-fluoro, 2-chloro, 4-fluoro, 4-chloro,2,4-difluoro, 2-methyl-4-chloro, or 2-methyl-4-fluoro; ortri-substituted in the 2,4,6-position such as 2,4,6-trifluoro. Anotherembodiment of the invention is the substitution of the phenyl ring inthe 3-position, such as with a halogen derivative, producing a3-position, 2,3-disubstitution, or a 3,4-disubstitution.

Suitably, when R₁ is a heteroaryl moiety, the ring is not attached tothe pharmacophore via one of the heteroatoms, such as nitrogen to form acharged ring. For instance, a pyridinyl ring would be attached through acarbon atom to yield a 2-, 3- or 4-pyridyl moiety, which is optionallysubstituted.

Suitably, v is 0 or an integer having a value of 1 or 2.

Suitably, Z is oxygen or sulfur.

Suitably, R_(a′) is C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl,arylC₁₋₄ alkyl, heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl,heterocyclylC₁₋₄ alkyl, (CR₁₀R₂₀)_(v)OR₇, (CR₁₀R₂₀)_(v)S(O)_(m)R₇,(CR₁₀R₂₀)_(v)NR₁₀S(O)₂R₇, or (CR₁₀R₂₀)_(v)NR₄R₁₄; and wherein the aryl,arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted.

Suitably, R₄ and R₁₄ are each independently selected from hydrogen,optionally substituted C₁₋₄ alkyl, optionally substituted aryl,optionally substituted aryl-C₁₋₄ alkyl, optionally substitutedheteroaryl, optionally substituted heteroaryl-C₁₋₄ alkyl.

The R₄ and R₁₄ moieties may be optionally substituted, one or moretimes, preferably 1 to 4 times independently by halogen, such asfluorine, chlorine, bromine or iodine; hydroxy; hydroxy substitutedC₁₋₁₀alkyl; C₁₋₁₀ alkoxy, such as methoxy or ethoxy; halosubstitutedC₁₋₁₀ alkoxy; S(O)m alkyl, such as methyl thio, methylsulfinyl or methylsulfonyl; aldehydes (—C(O)), or a ketone, such as —C(O)R₆, such asC(O)C₁₋₁₀alkyl or C(O)aryl; amides, such as C(O)NR_(4′)R₁₄′, orNR_(4′)C(O)C₁₋₁₀alkyl, or NR_(4′)C(O)aryl; NR_(4′)R_(14′), whereinR_(4′) and R_(14′) are each independently hydrogen or C₁₋₄ alkyl, orwherein the R_(4′)R_(14′) can cyclize together with the nitrogen towhich they are attached to form a 5 to 7 membered ring which optionallycontains an additional heteroatom selected from O/N/S; cyano, nitro,C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, or C₃₋₇cycloalkyl C₁₋₁₀ alkyl group, suchas methyl, ethyl, propyl, isopropyl, t-butyl, etc. or cyclopropylmethyl; halosubstituted C₁₋₁₀ alkyl, such CF₂CF₂H, CH₂CF₃, or CF₃; anoptionally substituted aryl, such as phenyl, or an optionallysubstituted arylalkyl, such as benzyl or phenethyl, wherein these arylcontaining moieties may themselves also be substituted one to two timesby halogen; hydroxy; hydroxy substituted alkyl; C₁₋₁₀ alkoxy;S(O)_(m)alkyl; amino, mono & di-substituted C₁₋₄ alkyl amino; C₁₋₄alkyl, or CF₃.

Suitably, R₅ is hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl orNR₄R₁₄, excluding the moieties SR₅ being SNR₄R₁₄, S(O)₂R₅ being SO₂H andS(O)R₅ being SOH.

Suitably, R₆ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,heterocyclyl C₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl orheteroarylC₁₋₁₀ alkyl, wherein these moieties may be optionallysubstituted.

Suitably, R₇ is C₁₋₆alkyl, aryl, arylC₁₋₆alkyl, heterocyclic,heterocyclylC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆alkyl; and whereineach of these moieties may be optionally substituted.

Suitably, R₈ is hydrogen, C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl,arylC₁₋₄ alkyl, heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl,heterocyclylC₁₋₄ alkyl, (CR₁₀R₂₀)_(t)OR₇, (CR₁₀R₂₀)_(t)S(O)_(m)R₇,(CR₁₀R₂₀)_(t)NR₁₀S(O)₂R₇, or (CR₁₀R₂₀)_(t)NR₄R₁₄; and where thecycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl,heterocyclic and heterocyclic alkyl moieties may be optionallysubstituted.

Suitably, t is an integer having a value of 1 to 3.

Suitably, R₉ is hydrogen, C(Z)R₆, optionally substituted C₁₋₁₀ alkyl,optionally substituted aryl or optionally substituted aryl-C₁₋₄ alkyl.

Suitably, R₁₀ and R₂₀ are independently selected from hydrogen or a C₁₋₄alkyl.

Suitably, R₁₁ is C₁₋₄ alkyl, halo-substituted C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylC₁₋₄ alkyl,heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl, heterocyclylC₁₋₄ alkyl,(CR₁₀R₂₀)_(t)OR₇, (CR₁₀R₂₀)_(t)S(O)_(m)R₇, (CR₁₀R₂₀)_(t) NR₁₀S(O)₂R₇, or(CR₁₀R₂₀)_(v)NR₄R₁₄; an wherein the aryl, arylalkyl, heteroaryl,heteroaryl alkyl, heterocyclyl, and heterocyclylalkyl moieties may beoptionally substituted.

Suitably m is 0 or an integer having a value of 1 or 2.

Suitably, R₃ is an optionally substituted C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl,C₃₋₇ cycloalkylC₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroarylC₁₋₁₀alkyl,or heterocyclylC₁₋₁₀ alkyl moiety, which moieties are optionallysubstituted. The moieties may be optionally substituted one or moretimes, suitably 1 to 4 times, independently by C₁₋₁₀ alkyl,halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀ alkyl, C₅₋₇cycloalkenyl,C₅₋₇cycloalkenylC₁₋₁₀ alkyl, halogen, cyano, nitro, (CR₁₀R₂₀)_(n)OR₆,(CR₁₀R₂₀)_(n)SH, (CR₁₀R₂₀)_(n)S(O)_(m)R₇, (CR₁₀R₂₀)_(n)NR₁₀S(O)₂R₇,(CR₁₀R₂₀)_(n)NR₄R₁₄, (CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n)S(O)₂NR₄R₁₄,(CR₁₀R₂₀)_(n)C(Z)R₆, (CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆,(CR₁₀R₂₀)_(n)C(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)R₆,(CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₀)NR₄R₁₄, (CR₁₀R₂₀)_(n)OC(Z)NR₄R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₄R₁₄, or (CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₇.

In one embodiment, the optional substituents on the R₃ moieties areindependently selected from halogen, alkyl, hydroxy, alkoxy, cyano,nitro, amino, or halosubstituted alkyl, suitably halogen, or alkyl.

Yet in another embodiment, R₃ is an optionally substituted C₁₋₁₀ alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylalkyl, aryl, or aryl C₁₋₁₀ alkyl; inanother embodiment R₃ is an optionally substituted C₁₋₁₀ alkyl, aryl, oraryl C₁₋₁₀ alkyl.

Suitably, when the R₃ moiety is an aryl ring, it is an optionallysubstituted phenyl ring. The ring may be optionally substituted one ormore times by halogen, C₁₋₄ alkyl, or halo-substituted-C₁₋₄ alkyl. Morepreferably, the phenyl ring is substituted in the 2, 4, or 6-position,or di-substituted in the 2,4-position, such as 2-fluoro, 2-chloro,4-fluoro, 4-chloro, 2,4-difluoro, 2-methyll-4-chloro, or2-methyl-4-fluoro; or tri-substituted in the 2,4,6-position, such as2,4,6-trifluoro.

Suitably, n is 0, or an integer having a value of 1 to 10.

Suitably, X is R₂, OR₂, S(O)_(m)R₂, (CH₂)_(n)N(R₁₀)S(O)_(m)R₂,(CH₂)_(n)N(R₁₀)C(O)R₂, (CH₂)_(n)NR₄R₁₄, NR₂(CH₂)_(n)NR₄R₁₄,O(CH₂)_(n)NR₄R₁₄, S(CH₂)_(n)NR₄R₁₄, (CH₂)_(n)J, NR₂(CH₂)_(n)J,O(CH₂)_(n)J, S(CH₂)_(n)J, or (CH₂)_(n)N(R₂)₂. In another embodiment whenX is R₂, then R₂ is the moiety X₁ (CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), orC(A₁)(A₂)(A₃).

Suitably, J is a heteroaryl ring, optionally substituted one or moretimes, suitably 1 to 3 times, as defined herein.

Suitably, R₂ is independently selected from hydrogen, halogen,optionally substituted C₁₋₁₀ alkyl, optionally substituted aryl,optionally substituted arylC₁₋₁₀alkyl, optionally substitutedheteroaryl, optionally substituted heteroarylC₁₋₁₀ alkyl, or R₂ is themoiety X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or C(A₁)(A₂)(A₃).

The R₂ moieties, excluding hydrogen, may be optionally substituted oneor more times, preferably 1 to 4 times, independently by C₁₋₁₀ alkyl,halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl C₅₋₇cycloalkenyl, C₅₋₇ cycloalkenylC₁₋₁₀ alkyl, halogen, —C(O), cyano, nitro, (CR₁₀R₂₀)_(n)OR₆,(CR₁₀R₂₀)_(n)SH, (CR₁₀R₂₀)_(n)S(O)_(m)R₇, (CR₁₀R₂₀)_(n)NR₁₀S(O)₂R₇,(CR₁₀R₂₀)_(n)NR₄R₁₄, (CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n)S(O)₂NR₄R₁₄,(CR₁₀R₂₀)_(n)C(Z)R₆, (CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆,(CR₁₀R₂₀)_(n)C(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)R₆,(CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₀)NR₄R₁₄, (CR₁₀R₂₀)_(n)C(═NOR₆)NR₄R₁₄,(CR₁₀R₂₀)_(n)OC(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₄R₁₄, or(CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₇.

In another emobdiment X is R₂, and R₂ is OR₂, (CH₂)_(n)N(R₂)₂ or(CH₂)_(n)NR₄R₁₄ or R₂ is the moiety X₁ (CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃).Suitably when X is (CH₂)_(n)N(R₂)₂, R₂ is (CR₁₀R₂₀)_(n)NR₄R₁₄ or(CR₁₀R₂₀)_(n)NR₁₀C(Z)R₆.

Suitably X₁ is N(R₁₀), O, S(O)_(m), or CR₁₀R₂₀. Preferably, X₁ isN(R₁₀), or oxygen.

Suitably, q is 0 or an integer having a value of 1 to 10.

Suitably, A₁ is an optionally substituted C₁₋₁₀ alkyl.

Suitably, A₂ is an optionally substituted C₁₋₁₀ alkyl.

Suitably, A₃ is hydrogen or is an optionally substituted C₁₋₁₀ alkyl.

The A₁, A₂, and A₃ C₁₋₁₀ alkyl moieties may optionally substituted,independently, one or more times, suitably from 1 to 4 times, byhalogen, such as chlorine, fluorine, bromine, or iodine;halo-substituted C₁₋₁₀alkyl, such as CF₃, or CHF₂CF₃; C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl,C₅₋₇cycloalkenyl, C₅₋₇ cycloalkenylC₁₋₁₀alkyl, (CR₁₀R₂₀)_(n)OR₆,(CR₁₀R₂₀)_(n)SH, (CR₁₀R₂₀)_(n)S(O)_(m)R₇, (CR₁₀R₂₀)_(n)NR₁₀S(O)₂R₇,(CR₁₀R₂₀)_(n)NR₄R₁₄, (CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n)S(O)₂NR₄R₁₄,(CR₁₀R₂₀)_(n)C(Z)R₆, (CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆,(CR₁₀R₂₀)_(n)C(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)R₆,(CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₀)NR₄R₁₄, (CR₁₀R₂₀)_(n)OC(Z)NR₄R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₄R₁₄, or (CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₇.

Suitably, one or more of A₁ to A₃ substituents is substituted with(CR₁₀R₂₀)_(n)OR₆; and R₆ is suitably hydrogen.

In another embodiment the C(A₁)(A₂)(A₃) group is CH(CH₂OH)₂, orC(CH₃)(CH₂OH)₂, X₁ (CR₁₀R₂₀)_(q)CH(CH₂OH)₂, orX₁(CR₁₀R₂₀)_(q)C(CH₃)(CH₂OH)₂; and X₁ is suitably oxygen or nitrogen.

Suitably, G₁ and G₂ are independently selected from is N, or C—X₂,provided that G₁ and G₂ are not both nitrogen.

X₂ is independently selected from hydrogen, halogen, or C₁₋₄alkyl.

Compounds of Formula (I) and (Ia) wherein G₁ is CH or C(C₁₋₄alkyl), andG₂ is nitrogen, are respectively designated as1,5,7-trisubstituted-1,8-napthyridin-2(1H)-one compounds, and are alsoreferred to herein as compounds of Formula (II) and (IIa).

Accordingly compounds of Formula (II) and (IIa) are represented by thestructure:

wherein

-   R₁ is an optionally substituted aryl or an optionally substituted    heteroaryl ring;-   X is R₂, OR₂, S(O)_(m)R₂, (CH₂)_(n)N(R₁₀)S(O)_(m)R₂,    (CH₂)_(n)N(R₁₀)C(O)R₂, (CH₂)_(n)NR₄R₁₄, NR₂(CH₂)_(n)NR₄R₁₄,    O(CH₂)_(n)NR₄R₁₄, S(CH₂)_(n)NR₄R₁₄, (CH₂)_(n)J, NR₂(CH₂)_(n)J,    O(CH₂)_(n)J, S(CH₂)_(n)J, or (CH₂)_(n)N(R₂)₂;-   J is an optionally substituted heteroaryl ring;-   n is 0 or an integer having a value of 1 to 10;-   m is 0 or an integer having a value of 1 or 2;-   q is 0 or an integer having a value of 1 to 10;-   R₂ is hydrogen, C₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,    heteroarylC₁₋₁₀ alkyl which moieties are all optionally substituted,    or R₂ is the moiety X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or C(A₁)(A₂)(A₃);-   X₁ is N(R₁₀), O, S(O)_(m), or CR₁₀R₂₀;-   X₂ is independently hydrogen, halogen or C₁₋₄ alkyl;-   A₁ is an optionally substituted C₁₋₁₀ alkyl;-   A₂ is an optionally substituted C₁₋₁₀ alkyl;-   A₃ is hydrogen or is an optionally substituted C₁₋₁₀ alkyl;-   G₁ is C—X₂;-   R₃ is a hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylC₁₋₄alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,    heteroarylC₁₋₁₀ alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl    moiety, which moieties are optionally substituted; provided that R₃    is not hydrogen or methyl when G₁ is nitrogen, G₂ is C—X₂, X₂ is    hydrogen, R₁ is an optionally substituted phenyl, X is R₂ and R₂ is    hydrogen;-   R₄ and R₁₄ are each independently selected from hydrogen, optionally    substituted C₁₋₄ alkyl, optionally substituted aryl, or optionally    substituted aryl-C₁₋₄ alkyl, arylC₁₋₁₀ alkyl, heteroaryl or    heteroarylC₁₋₁₀ alkyl, wherein each of these moieties may be    optionally substituted;-   R₁₀ and R₂₀ are independently selected from hydrogen or C₁₋₄alkyl;    or a pharmaceutically acceptable salt thereof.

Suitably, in another embodiment of the invention, when X is R₂, then R₂is C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl, aryl, arylC₁₋₁₀ alkyl,heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or a heterocyclylC₁₋₁₀alkyl moiety, or R₂ is the moiety X₁(CR₁₀R₂₀)_(q)—C(A₁)(A₂)(A₃), orC(A₁)(A₂)(A₃).

Representative species of Formula (II) and (IIa) are:

-   1,5-bis(4-fluorophenyl)[1,8]naphthyridin-2(1H)-oneX; and-   5-(2,4-difluorophenyl)-1-(4-fluorophenyl)[1,8]naphthyridin-2(1H)-one,-   1,5-bis(2-chlorophenyl)-7-{[2-(isopropylamino)ethyl]amino}[1,8]naphthyridin-2(1H-one;-   1,5-bis(2-chlorophenyl)-7-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}[1,8]naphthyridin-2(1H-one;    or a pharmaceutically acceptable salt thereof.

Compounds of Formula (I) and (Ia) wherein G₂ is CH or C(C₁₋₄alkyl), andG₁ is nitrogen are respectively designated as 1,5,7trisubstituted-1,6-napthyridine-2-(1H)-one compounds and are alsoreferred to herein as compounds of Formula (III) and (IIIa).

Accordingly compounds of Formula (III) and (IIIa) are represented by thestructure:

wherein

-   R₁ is an optionally substituted aryl or an optionally substituted    heteroaryl ring;-   X is R₂, OR₂, S(O)_(m)R₂, (CH₂)_(n)N(R₁₀)S(O)_(m)R₂,    (CH₂)_(n)N(R₁₀)C(O)R₂, (CH₂)_(n)NR₄R₁₄, NR₂(CH₂)_(n)NR₄R₁₄,    O(CH₂)_(n)NR₄R₁₄, S(CH₂)_(n)NR₄R (CH₂)_(n)J, NR₂(CH₂)_(n)J,    O(CH₂)_(n)J, S(CH₂)_(n)J, or (CH₂)_(n)N(R₂)₂;-   J is an optionally substituted heteroaryl ring;-   n is 0 or an integer having a value of 1 to 10;-   m is 0 or an integer having a value of 1 or 2;-   q is 0 or an integer having a value of 1 to 10;-   R₂ is hydrogen, C₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,    heteroarylC₁₀ alkyl, which moieties are all optionally substituted,    or R₂ is the moiety X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or C(A₁)(A₂)(A₃);-   X₁ is N(R₁₀), O, S(O)_(m), or CR₁₀R₂₀;-   X₂ is independently hydrogen, halogen or C₁₋₄ alkyl;-   A₁ is an optionally substituted C₁₋₁₀ alkyl;-   A₂ is an optionally substituted C₁₋₁₀ alkyl;-   A₃ is hydrogen or is an optionally substituted C₁₋₁₀ alkyl;-   G₂ is C—X₂;-   R₃ is a hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylC₁₋₄alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,    heteroarylC₁₋₁₀ alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl    moiety, which moieties are optionally substituted; provided that R₃    is not hydrogen or methyl when G₁ is nitrogen, G₂ is C—X₂, X₂ is    hydrogen, R₁ is an optionally substituted phenyl, X is R₂ and R₂ is    hydrogen;-   R₄ and R₁₄ are each independently selected from hydrogen, optionally    substituted C₁₋₄ alkyl, optionally substituted aryl, or optionally    substituted aryl-C₁₋₄ alkyl, arylC₁₋₁₀ alkyl, heteroaryl or    heteroarylC₁₋₁₀ alkyl, wherein each of these moieties may be    optionally substituted;-   R₁₀ and R₂₀ are independently selected from hydrogen or C₁₋₄alkyl;    or    a pharmaceutically acceptable salt thereof.

Representative species of Formula (III) and (IIa) are:

-   7-Bromo-1,5-bis(2-chlorophenyl)-3,4-dihydro[1,6]naphthyridin-2(1H)-one;-   7-Bromo-1,5-bis(2-chlorophenyl)[1,6]naphthyridin-2(1H)-one;-   1,5-Bis(2-Chlorophenyl)-7-[(2-hydroxy-1-(hydroxymethyl)ethyl]-amino]-[1,6]naphthyridin-2(1H)-one;-   N-[2-[[1,5-bis(2-Chlorophenyl)-2-oxo-1,2-dihydro[1,6]naphthyridin-7-yl]amino]ethyl]acetamide;-   1,5-Bis(2-Chlorophenyl)-7-[(1H-imidazol-2-ylmethyl)amino][1,6]naphthyridin-2(1H)-one;-   1,5-Bis(2-Chlorophenyl)-7-[[2-(Isopropylamino)ethyl]amino][1,6]naphthyridin-2(1H)-one;-   1,5-Bis(2-Chlorophenyl)-7-amino-[1,6]naphthyridin-2(1H)-one;-   1,5-Bis(2-Chlorophenyl)-7-chloro-[1,6]naphthyridin-2(1H)-one;    or a pharmaceutically acceptable salt thereof.

Representative species of Formula (III) and (IIIa) wherein X is hydrogenare:

-   1-Benzyl-5-phenyl-1H-[1,6]naphthyridin-2-one;-   1,5-Diphenyl-1H-[1,6]naphthyridin-2-one; or    a pharmaceutically acceptable salt thereof.

Compounds of Formula (I) and (Ia) wherein both G₁ and G₂ are either CHor C(C₁₋₄alkyl), are respectively designated as 1,5,7-trisubstitutedquinoline-2(1H)-one compounds and are also referred to herein ascompounds of Formula (IV) and (IVa).

Accordingly compounds of Formula (IV) and (IVa) are represented by thestructure:

wherein

-   R₁ is an optionally substituted aryl or an optionally substituted    heteroaryl ring;-   X is R₂, OR₂, S(O)_(m)R₂, (CH₂)_(n)N(R₁₀)S(O)_(m)R₂,    (CH₂)_(n)N(R₁₀)C(O)R₂, (CH₂)_(n)NR₄R₁₄, NR₂(CH₂)_(n)NR₄R₁₄,    O(CH₂)_(n)NR₄R₁₄, S(CH₂)_(n)NR₄R_((CH) ₂)_(n)J, NR₂(CH₂)_(n)J,    O(CH₂)_(n)J, S(CH₂)_(n)J, or (CH₂)_(n)N(R₂)₂;-   J is an optionally substituted heteroaryl ring;-   n is 0 or an integer having a value of 1 to 10;-   m is 0 or an integer having a value of 1 or 2;-   q is 0 or an integer having a value of 1 to 10;-   R₂ is hydrogen, C₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,    heteroarylC₁₋₁₋₁₀ alkyl, which moieties are all optionally    substituted, or R₂ is the moiety X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or    C(A₁)(A₂)(A₃);-   X₁ is N(R₁₀), O, S(O)_(m), or CR₁₀R₂₀;-   X₂ is independently hydrogen, halogen or C₁₋₄ alkyl;-   A₁ is an optionally substituted C₁₋₁₀ alkyl;-   A₂ is an optionally substituted C₁₋₁₀ alkyl;-   A₃ is hydrogen or is an optionally substituted C₁₋₁₀ alkyl;-   G₁ and G₂ are independently C—X₂;-   R₃ is a hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylC₁₋₄alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,    heteroarylC₁₋₁₀ alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl    moiety, which moieties are optionally substituted;-   R₄ and R₁₄ are each independently selected from hydrogen, optionally    substituted C₁₋₄ alkyl, optionally substituted aryl, or optionally    substituted aryl-C₁₋₄ alkyl, arylC₁₋₁₀ alkyl, heteroaryl or    heteroarylC₁₋₁₀ alkyl, wherein each of these moieties may be    optionally substituted;-   R₁₀ and R₂₀ are independently selected from hydrogen or C₁₋₄alkyl;    provided that when    -   R₁ is phenyl, R₂ is methoxy substituted phenyl, X is        (CH₂)_(n)NR₄R₁₄, n is 0, R₄ and R₁₄ are other than both methyl;        a pharmaceutically acceptable salt thereof.

Suitably, when R₁ is a 2-chlorophenyl, or 2-Cl,4-F-phenyl and R₃ is a2,6-dichlorophenyl, and X is OR₂, then R₂ is other than methyl.Suitably, when R₁ and R₃ are both halo substituted phenyl rings, and Xis OR₂, then R₂ is other than C₁₋₁₀ alkyl.

Representative species of Formula (IV) and (IVa) are:

-   5-(2-fluorophenyl)-1-(4-flourophenyl)-2(1H)-quinolinone;-   5-(4-fluorophenyl)-1-(4-fluorophenyl)-2(1H)-quinolinone;-   5-(2,4-difluorophenyl)-1-(4-fluorophenyl)-2(1H)-quinolinone;-   5-(4-methylphenyl)-1-(4-fluorophenyl)-2(1H)-quinolinone;-   1,5-bis(2-chlorophenyl)-7-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-2(1H)-quinolinone;-   1,5-Bis(2-chlorophenyl)-7-{[2-(isopropylamino)ethyl]amino}-2(1H-quinolinone;-   6-bromo-1,5-bis(2-chlorophenyl)-7-(methyloxy)-2(1H)-quinolinone;    or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, compounds orpharmaceutical compositions of Formula (V) and (Va) compounds have beenfound to be useful treating a CSBP/RK/p38 kinase mediated disease in amammal in need thereof, comprising administering to said mammal aneffective amount of a compound of Formula (V) or (Va).

Compounds of Formula (V) and (Va) are represented by the structure:

wherein

-   R₁ is an optionally substituted aryl or an optionally substituted    heteroaryl ring;-   X is halogen, R₂, OR₂, S(O)_(m)R₂, (CH₂)_(n)N(R₁₀)S(O)_(m)R₂,    (CH₂)_(n)N(R₁₀)C(O)R₂, (CH₂)_(n)NR₄R₁₄, NR2(CH2)nNR4R14,    O(CH2)_(n)NR4R14, S(CH2)nNR4R14, (CH₂)_(n)J, NR2(CH2)nJ, O(CH2)nJ,    S(CH2)nJ, or (CH₂)_(n)N(R₂)₂;-   J is an optionally substituted heteroaryl ring;-   n is 0 or an integer having a value of 1 to 10;-   m is 0 or an integer having a value of 1 or 2;-   q is 0 or an integer having a value of 1 to 10;-   R₂ is hydrogen, C₁₋₁₀ alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,    heteroarylC₁₋₁₀ alkyl, which moieties are all optionally    substituted, or R₂ is the moiety X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or    C(A₁)(A₂)(A₃);-   X₁ is N(R₁₀), O, S(O)_(m), or CR₁₀R₂₀;-   X₂ is independently hydrogen, halogen or C₁₋₄ alkyl;-   A₁ is an optionally substituted C₁₋₁₀ alkyl;-   A₂ is an optionally substituted C₁₋₁₀ alkyl;-   A₃ is hydrogen or is an optionally substituted C₁₋₁₀ alkyl;-   G₁ and G₂ are independently selected from is N, or C—X₂, provided    that G₁ and G₂ are not both nitrogen;-   R₃ is an hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇    cycloalkylC₁₋₄alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,    heteroarylC₁₋₁₀ alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl    moiety, which moieties are optionally substituted;-   R₄ and R₁₄ are each independently selected from hydrogen, optionally    substituted C₁₋₄ alkyl, optionally substituted aryl, or optionally    substituted aryl-C₁₋₄ alkyl, arylC₁₋₁₀ alkyl, heteroaryl or    heteroarylC₁₋₁₀ alkyl, wherein each of these moieties may be    optionally substituted;-   R₉ is hydrogen, C(Z)R₆ or optionally substituted C₁₀ alkyl,    optionally substituted aryl or optionally substituted aryl-C₁₋₄    alkyl;-   R₁₀ and R₂₀ are independently selected from hydrogen or C₁₋₄alkyl;    or a pharmaceutically acceptable salt thereof.

Compounds of Formula (V) and (Va) include those of Formula (I) and (Ia)as well as compounds such as1-methyl-5-phenyl-1H-[1,6]naphthyridin-2-one and5-phenyl-1H-[1,6]naphthyridin-2-one which have also been found to beactive as inhibitors of the CSBP kinase.

As used herein, “optionally substituted” unless specifically definedshall mean such groups as halogen, such as fluorine, chlorine, bromineor iodine; hydroxy; hydroxy substituted C₁₋₁₀alkyl; C₁₋₁₀ alkoxy, suchas methoxy or ethoxy; halosubstituted C₁₋₁₀ alkoxy; S(O)m alkyl, such asmethyl thio, methylsulfinyl or methyl sulfonyl; —C(O); NR_(4′)R_(14′),wherein R_(4′) and R_(14′) are each independently hydrogen or C₁₋₄alkyl, such as amino or mono or -disubstituted C₁₋₄ alkyl or wherein theR_(4′)R_(14′) can cyclize together with the nitrogen to which they areattached to form a 5 to 7 membered ring which optionally contains anadditional heteroatom selected from 0/N/S; C₁₋₁₀ alkyl, C₃₋₇cycloalkyl,or C₃₋₇cycloalkyl C₁₋₁₀ alkyl group, such as methyl, ethyl, propyl,isopropyl, t-butyl, etc. or cyclopropyl methyl; halosubstituted C₁₋₁₀alkyl, such CF₂CF₂H, or CF₃; an optionally substituted aryl, such asphenyl, or an optionally substituted arylalkyl, such as benzyl orphenethyl, wherein these aryl containing moieties may also besubstituted one to two times by halogen; hydroxy; hydroxy substitutedalkyl; C₁₋₁₀ alkoxy; S(O)_(m)alkyl; amino, mono & di-substituted C₁₋₄alkyl amino, such as in the NR₄R₁₄ group; C₁₋₄ alkyl, or CF₃.

Suitable pharmaceutically acceptable salts are well known to thoseskilled in the art and include basic salts of inorganic and organicacids, such as hydrochloric acid, hydrobromic acid, sulphuric acid,phosphoric acid, methane sulphonic acid, ethane sulphonic acid, aceticacid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid,succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid,phenylacetic acid and mandelic acid.

In addition, pharmaceutically acceptable salts of compounds of Formula(I) may also be formed with a pharmaceutically acceptable cation, forinstance, if a substituent group comprises a carboxy moiety. Suitablepharmaceutically acceptable cations are well known to those skilled inthe art and include alkaline, alkaline earth, ammonium and quaternaryammonium cations.

The term ‘halo’ or “halogens” is used herein to mean the halogens,chloro, fluoro, bromo and iodo.

The term “C₁₋₁₀alkyl” or “alkyl” or “alkyl₁₋₁₀” is used herein to meanboth straight and branched chain radicals of 1 to 10 carbon atoms,unless the chain length is otherwise limited, including, but not limitedto, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,tert-butyl, n-pentyl and the like.

The term “cycloalkyl” is used herein to mean cyclic radicals, preferablyof 3 to 8 carbons, including but not limited to cyclopropyl,cyclopentyl, cyclohexyl, and the like.

The term “cycloalkenyl” is used herein to mean cyclic radicals,preferably of 5 to 8 carbons, which have at least one bond including butnot limited to cyclopentenyl, cyclohexenyl, and the like.

The term “alkenyl” is used herein at all occurrences to mean straight orbranched chain radical of 2-10 carbon atoms, unless the chain length islimited thereto, including, but not limited to ethenyl, 1-propenyl,2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.

The term “aryl” is used herein to mean phenyl and naphthyl.

The term “heteroaryl” (on its own or in any combination, such as“heteroaryloxy”, or “heteroaryl alkyl”) is used herein to mean a 5-10membered aromatic ring system in which one or more rings contain one ormore heteroatoms selected from the group consisting of N, O or S, suchas, but not limited, to pyrrole, pyrazole, furan, pyran, thiophene,quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, pyridazine,pyrazine, uracil, oxadiazole, oxazole, isoxazole, oxathiadiazole,thiazole, isothiazole, thiadiazole, tetrazole, triazole, indazole,imidazole, or benzimidazole.

The term “heterocyclic” (on its own or in any combination, such as“heterocyclylalkyl”) is used herein to mean a saturated or partiallyunsaturated 4-10 membered ring system in which one or more rings containone or more heteroatoms selected from the group consisting of N, O, S,or S(O)m, and m is 0 or an integer having a value of 1 or 2; such as,but not limited to, the saturated or partially saturated versions of theheteroaryl moieties as defined above, such as tetrahydropyrrole,tetrahydropyran, tetrahydrofuran, tetrahydrothiophene (includingoxidized versions of the sulfur moiety), pyrrolidine, piperidine,piperazine, morpholine, thiomorpholine (including oxidized versions ofthe sulfur moiety), or imidazolidine.

The term “aralkyl” or “heteroarylalkyl” or “heterocyclicalkyl” is usedherein to mean C₁₋₄ alkyl as defined above attached to an aryl,heteroaryl or heterocyclic moiety as also defined herein unlessotherwise indicate.

The term “sulfinyl” is used herein to mean the oxide S(O) of thecorresponding sulfide, the term “thio” refers to the sulfide, and theterm “sulfonyl” refers to the fully oxidized S(O)₂ moiety.

The term “aroyl” is used herein to mean C(O)Ar, wherein Ar is as phenyl,naphthyl, or aryl alkyl derivative such as defined above, such groupinclude but are not limited to benzyl and phenethyl.

The term “alkanoyl” is used herein to mean C(O)C₁₋₁₀ alkyl wherein thealkyl is as defined above.

It is recognized that the compounds of the present invention may existas stereoisomers, regioisomers, or diastereiomers. These compounds maycontain one or more asymmetric carbon atoms and may exist in racemic andoptically active forms. All of these individual compounds, isomers, andmixtures thereof are included within the scope of the present invention.

Exemplified compounds of the compounds of this invention include theracemates, or optically active forms of the compounds of the workingexamples herein, and pharmaceutically acceptable salts thereof.

Methods of Manufacture

The compounds of Formula (I), (Ia), may be obtained by applyingsynthetic procedures, described herein. The synthesis provided for isapplicable to producing compounds of Formula (I), (Ia), having a varietyof different R₁, R₂, Y, X, and R₃ groups which are reacted, employingoptional substituents which are suitably protected, to achievecompatibility with the reactions outlined herein. Subsequentdeprotection, in those cases, then affords compounds of the naturegenerally disclosed. While a particular formula with particularsubstituent groups is shown herein, the synthesis is applicable to allformulas and all substituent groups herein.

Once the nucleus has been established, further compounds of Formula (I),(Ia), (II) and (IIa) may be prepared by applying standard techniques forfunctional group interconversion, well known in the art. For instance:C(O)NR₄R₁₄ from CO₂CH₃ by heating with HNR₄R₁₄ in CH₃OH with or withoutcatalytic or stoichiometric metal cyanide or Aluminum trimethyl, e.g.NaCN; OC(O)R₃ from OH with e.g., ClC(O)R₆ in bases such as triethylamineand pyridine; NR₁₀—C(S)NR₄R₁₄ from NHR₁₀ with an alkylisothiocyanate, orthiocyanic acid and ClC(S)NR₄R₁₄; NR₁₀C(O)OR₆ from NHR₁₀ with an alkylor aryl chloroformate; NR₁₀C(O)NR₄H from NHR₁₀ by treatment with anisocyanate, e.g. R₄N═C═O; NR₁₀—C(O)R₆ from NHR₁₀ by treatment withCl—C(O)R₆ in pyridine; C(═NR₁₀)NR₄R₁₄ from C(NR₄R₁₄)S with H₃NR₁₀ ⁺OAc⁻by heating in alcohol; C(NR₄R₁₄)SR₆ from C(S)NR₄R₁₄ with R₆—I in aninert solvent, e.g. acetone; NR₁₀SO₂R₇ from NHR₁₀ by treatment withClSO₂R₇ by heating in bases such as pyridine; NR₁₀C(S)R₆ from NR₁₀C(O)R₆by treatment with Lawesson's reagent[2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide];NR₁₀SO₂CF₃ from NHR₁₀ with triflic anhydride and base wherein R₃, R₆,R₁₀, R₄ and R₁₄ are as defined in Formula (I) herein.

Precursors of the groups R₁, R₂ and R₃, can be other R₁, R₂ and R₃, etcgroups that may be interconverted by applying standard techniques forfunctional group interconversion. For example wherein a moiety is a halosubstituted C₁₋₁₀ alkyl can be converted to the corresponding C₁₋₁₀alkylN₃ derivative by reacting with a suitable azide salt, andthereafter if desired can be reduced to the corresponding C₁₋₁₀alkylNH₂compound, which in turn can be reacted with R₇S(0)₂X wherein X is halo(e.g., chloro) to yield the corresponding C₁₋₁₀alkylNHS(0)₂R₇ compound.

Alternatively wherein the moiety is a halo-substituted C₁₋₁₀-alkyl itcan be reacted with an amine R₄R₁₄NH to yield the correspondingC₁₋₁₀-alkylNR₄R₁₄ compound, or can be reacted with an alkali metal saltof R₇SH to yield the corresponding C₁₋₁₀alkylSR₇ compound.

As noted above, it may be desirable during the synthesis of thecompounds of this invention, to derivatize reactive functional groups inthe molecule undergoing reaction so as to avoid unwanted side reactions.Functional groups such as hydroxy, amino, an acid groups typically areprotected with suitable groups that can be readily removed when desired.Suitable common protecting groups for use with hydroxyl groups andnitrogen groups are well known in the art and described in manyreferences, for instance, Protecting Groups in Organic Synthesis, Greeneet al., John Wiley & Sons, New York, N.Y., (2nd edition, 1991 or theearlier 1981 version). Suitable examples of hydroxyl protecting groupsinclude ether forming groups such as benzyl, and aryl groups such astert-butoxycarbonyl (Boc), silyl ethers, such as t-butyldimethyl ort-butyidiphenyl, and alkyl ethers, such as methyl connected by an alkylchain of variable link, (CR₁₀R₂₀)_(n). Amino protecting groups mayinclude benzyl, aryl such as acetyl and trialkylsilyl groups. Carboxylicacid groups are typically protected by conversion to an ester that caneasily be hydrolyzed, for example, trichloroethyl, tert-butyl, benzyland the like.

Pharmaceutically acceptable acid addition salts of compounds of Formula(I), (Ia), (II) and (IIa) may be obtained in known manner, for exampleby treatment thereof with an appropriate amount of acid in the presenceof a suitable solvent.

An illustration of the preparation of compounds of the present inventionare shown in the schemes below.

1H-[1,6]Naphthyridin-2-ones may be prepared by the route depicted inScheme 1. The starting material 1-Scheme 1 may be obtained from thecommercially available 2-amino-3-methylpyridine by known literatureprocedures, such as those noted in International Publication No. WO02/058695 A1. R₁ could be aryl, cyclic or noncyclic alkyl group. Theintermediate 4-Scheme 1 may be produced by two different procedures. Inthe first procedure, coupling of the aryl bromide 1-Scheme 1 withmalonate or mono malonate in the presence of sodium hydride in THFafford the desired compound 2-Scheme 1 after the required saponificationand decarboxylation. Other suitable bases, including but not limited tolithium hydride, potassium hydride, sodium ethoxide, butyl lithium, mayalso be used in an appropriate organic solvent, including but notlimited to DMF, diethyl ether, dioxane. The carboxylic acid 2-Scheme 1may be then converted to the corresponding activated carboxylate. Forexample the acid chloride may be prepared, using oxalyl chloride orthionyl chloride, or related reagent and coupled with the requisiteamine to provide the amide 4-Scheme 1.

In the second procedure, the aryl bromide 1-Scheme 1 may be treated withalkyl acetate such as tert-butyl acetate or ethyl acetate in thepresence of suitable bases, including but are not limited to LDA, BuLi,KHMDS, NaHMDS, to provide the desired ester 3-Scheme 1. If the ester wastert-butyl, it may be cleaved with TFA to the carboxylic acid, which maybe converted to the methyl ester with any one of a number of knownmethods such as with trimethylsilyldiazomethane. The ester may be thenconverted to the amide 4-Scheme 1 by treatment with AlMe₃ and thecorresponding amine.

The cyclization of the amide 4-Scheme 1 to afford 5-Scheme 1 may becompleted by heating the reaction in DMF with copper(I) iodide andpotassium carbonate. The reaction had fewer impurities and was shortenedin duration if heating was accompanied by microwave irradiation. Othersuitable bases, including, but not limited to lithium-hydride, sodiumhydride, pyridine, may be used in an appropriate organic solvent such asmethyl sulfoxide, ethoxyethanol (see for example Boschelli, D. H. et al.J. Med. Chem. 2001, 44, 822). Alternatively, the cyclization reactionmay also be performed using a palladium catalyst such as Pd₂(dba)₃ withthe suitable phosphorous ligands, including but not limited totri(tert-butyl)phosphine, (o-biphenyl)P(t-Bu)₂, (o-biphenyl)PCy₂ (Seefor example Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35-37.).

Displacements of the bromide 5-Scheme 1 to the product 6-Scheme 1 werecompleted with an excess of amine in polar solvent, including but notlimited to N-methylpyrrolidin-2-one (NMP), ethanol, methanol, DMSO, withor without copper (I) salt, and at varying temperatures depending uponthe nucleophilicity of the amine (see for example Terauchi, H. et al.Chem. Pharm. Bull. 2001, 45,1027). The reaction had fewer impurities andwas shortened in duration if heating was accompanied by microwaveirradiation. The bromide may also be displaced with a substitutedarylamine, or heteroarylamine at elevated temperatures, sometimesrequiring formation of the aryl or heteroarylamine anion with sodiumhydride, or other suitable base, in DMSO. Alternatively, thedisplacements may also be performed using a palladium catalyst such asbut not limited to tetrakis(triphenylphosphine)-palladium(0) with thesuitable base, including but not limited to potassium t-butoxide, sodiumcarbonate, cesium carbonate (see for example Grasa, G. A. et al. J. Org.Chem. 2001, 66, 7729).

Oxidation of 6-Scheme 1 to 8-Scheme 1 could be achieved via abromination and elimination process with N-bromosuccinimide and AIBN.This process could also be completed via an α-oxidation of the amide6-Scheme 1 by using a suitable oxidation reagent such as Davis reagent(Davis, F. A.; Sheppard, A. C. Tetrahedron 1989, 45, 5703), followed byan elimination to provide 8-Scheme 1. MnO₂ was also an effective reagentfor dehydrogenation to 8-Scheme 1. DDQ also would carry out thistransformation. Alternatively, bromide 5-Scheme 1 could first bedehydrogenated to afford 7-Scheme 1 by the same procedures as describedabove for the conversion of 6 to 8 in Scheme 1. The bromide 7-Scheme 1was then be displaced with amines in the same manner as the conversionof 5 to 7 in Scheme 1. For example, treatment of 7-Scheme 1 with primaryalkylamines in NMP at 220° for 30 min. with microwave irradiationafforded the aminated analogs 8-Scheme 1, R₄═H, R₁₄=alkyl.

1H-[1,6]Naphthyridin-2-ones may also be prepared from a suitable1-substitututed-1,3-butanedione 1-Scheme 2. For purposes herein R₂ is R₃in Formula (I) and (Ia). Some of the substututed-1,3-butanediones arecommercially available; while others can be readily prepared followingliterature procedures, such as the preparation of1-aryl-1,3-butanediones from aryl esters as exemplified by Chaney et.al, J. Org. Chem. 1951, 57-58. Heteroaryl-1,3-butanediones have alsobeen prepared from heteroaryl esters as exemplified by Ferenczy,Monatsh. Chem. 1897, 674. Cycloalkyl-1,3-butanediones have been preparedfrom cycloalkyl methyl ketones as exemplified by Sprague et. al., J. Am.Chem. Soc. 1934, 2655-2666. Alkyl-1,3 butanediones have been preparedfrom alkyl methylketones as exemplified by Adams et. al, J. Am. Chem.Soc. 1945, 285. Reaction of compound 1-Scheme 2 with ammonium hydroxidein a suitable solvent such as methanol gives the imine 2-Scheme 2.Reaction of imine 2-Scheme 2 with an acetylenic ester such as methylpropiolate in a suitable solvent such as DMF at elevated temperaturegives the 5-substituted-6-methyl-2(1H)-pyridinone 3-Scheme 2. Compound3-Scheme 2 is reacted with N,N-dimethylformamide dimethyl acetal in asuitable solvent such as DMF at elevated temperature to give thecorresponding 5-substituted-6-[2-dimethylamino)ethenyl]-2(1H)-pyridinone4-Scheme 2. Conversion of compound 4-Scheme 2 to the5-substituted-1H-[1,6]naphthyridin-2-one 5-Scheme 2 is accomplished byheating compound 4-Scheme 2 with ammonium acetate in a suitable solventsuch as DMF. Alkylation of compound 5-Scheme 2 with a suitablealkylating agent R₂X such as an alkyl halide in a suitable solvent suchas DMF or acetone, with a suitable base such as potassium carbonate orsodium hydride gives the 1H-[1,6]Naphthyridin-2-ones 6-Scheme 2. Thegeneral procedure for conversion of compounds 1-Scheme 2 into Compounds6-Scheme 2 was exemplified by Lesher et al., in U.S. Pat. No. 4,560,691.Alternatively the compound 6-Scheme 2 where R₂ is aryl or heteroaryl canbe prepared from compound 5-Scheme 2 by reacting with an arylboronicacid in the presence of a suitable catalyst such as cupric acetate and asuitable base such as triethylamine or pyridine. This procedure wasexemplified by Chan et. al., Tett. Lett. 1998, 2933-2936.

1H-[1,8]Naphthyridin-2-ones may be prepared by the route depicted inScheme 3. The starting material 1-Scheme 3 may be obtained by knownliterature procedures, such as those noted in International PublicationNo. WO 02/058695 A1. R₁ could be aryl, cyclic or noncyclic alkyl group.

The intermediate 4-Scheme 3 may be produced by two different procedures.In the first procedure, coupling of 1-Scheme 3 with malonate or monomalonate in the presence of sodium hydride in THF affords the desiredcompound 2-Scheme 3 after the required saponification anddecarboxylation. Other suitable base, includes but are not limited tolithium hydride, potassium hydride, sodium ethoxide, butyl lithium, usedin an appropriate organic solvent, including but not limited to DMF,diethyl ether, dioxane. The carboxylic acid 2-Scheme 3 may be thenconverted to the corresponding activated carboxylate. For example theacid chloride may be prepared, using oxalyl chloride or thionylchloride, or related reagent to afford the activated carboxylate whichmay be coupled with the requisite amine to provide the amide 4-Scheme 3.

In the second procedure, 1-Scheme 3 is treated with alkyl acetate suchas tert-butyl acetate or ethyl acetate in the presence of suitablebases, including but are not limited to LDA, BuLi, KHMDS, NaHMDS, toprovide the desired ester 3-Scheme 3. If the ester is tert-butyl, it maybe cleaved with TFA to the carboxylic acid, which may be converted tothe methyl ester by any one of a number of known methods such as withtrimethylsilyldiazomethane. The ester is then converted to the amide4-Scheme 3 by treatment with AlMe₃ and the corresponding amine.

The cyclization of the amide 4-Scheme 3 is completed by heating thereaction in DMF with copper(I) iodide and potassium carbonate to afford5-Scheme 3. Other suitable base, includes but are not limited to lithiumhydride, sodium hydride, pyridine, used in an appropriate organicsolvent such as methyl sulfoxide, ethoxyethanol (see for exampleBoschelli, D. H. et al. J. Med. Chem. 2001, 44, 822). Alternatively, thecyclization reaction may also be performed using a palladium catalystsuch as Pd₂(dba)₃ with the suitable phosphorous ligands, including butnot limited to tri(tert-butyl)phosphine, (o-biphenyl)P(t-Bu)₂,(o-biphenyl)PCy₂ (See for example Yang, B. H.; Buchwald, S. L. Org.Lett. 1999,1,35-37.).

Oxidation of 5-Scheme 3 to 6-Scheme 3 could be achieved via abromination and elimination process with N-bromosuccinimide and AIBN.This process could also be completed via an α-oxidation of 5-Scheme 3 byusing a suitable oxidation reagent such as Davis reagent (Davis, F. A.;Sheppard, A. C. Tetrahedron 1989, 45, 5703), followed by an eliminationto provide 6-Scheme 3. MnO₂ is also an effective reagent for thistransformation, as is also DDQ.

Displacements of the chloride in 6-Scheme 3 to 8-Scheme 3 were completedwith an excess of amine in polar solvent, including but not limited toN-methyl pyrrolidin-2-one (NMP), ethanol, methanol, DMSO, with orwithout copper (I) salt, and at varying temperatures depending upon thenucleophilicity of the amine (see for example Terauchi, H. et al. Chem.Pharm. Bull. 2001, 45, 1027). The reaction had fewer impurities and wasshortened in duration if heating was accompanied by microwaveirradiation. The chloride may also be displaced with a substitutedarylamine, or heteroarylamine at elevated temperatures, sometimesrequiring formation of the aryl or heteroarylamine anion with sodiumhydride, or other suitable base, in DMSO. Alternatively, thedisplacements may also be performed using a palladium catalyst such asbut not limited to tetrakis(triphenyl-phosphine)palladium(0) with thesuitable base, including but not limited to t-butoxide, sodiumcarbonate, cesium carbonate (see for example Grasa, G. A. et al. J. Org.Chem. 2001, 66, 7729).

Alternatively, the conversion of 5-Scheme 3 to 8-Scheme 3 could beeffected by reversal of the sequence of the above two reactions, firstdisplacing the chloride as described above to afford 7-Scheme 3,followed by the dehydrogenation step under the previously describedconditions to afford 8-Scheme 3.

a, pivaloyl chloride/Et₃N/CH₂Cl₂; b, i) n-BuLi/THF ii) DMF; c,LDA/THF/tert-butyl acetate; d, 3M HCl; e, ArB(OH)₂/(Ph₃P)₄Pd/aq.K₂CO₃/ethylene glycol dimethyl ether; f, 4-fluorophenylboronicacid/Cu(OAc)₂/pyridine/Et₃N/CH₂Cl₂/powdered 4 Å sieves.

Another synthesis of the 1H-[1,8]Naphthyridin-2-ones is depicted inScheme 4. 4-Chloro-2-aminopyridine, 1-Scheme 4, (prepared by theliterature procedure: Townsend, L. B. et al Synthetic Commun. 1997 27,861-870) was acylated with pivaloyl chloride and triethylamine inmethylene chloride to afford 2-Scheme 4. This transformation is readilyachieved with pivaloyl chloride or other pivalic acid activated estersunder a variety of other well known conditions for amide formation suchas those described in standard textbooks of organic synthesis (forexample March J. Advanced Organic Chemistry. Reactions, Mechanims andStructure 1985, 3rd ed. 370-371).

The pivalamide was then regioselectively lithiated at the 3 positionwith n-butyl lithium and formylated with dimethylformamide (DMF)affording 3-Scheme 4. This stereoselectivity is likely aided bycoordination of the lithium with the amide (for example see Tamura, Y.et al., Chem Pharm Bull. 1982, 30.1257-1262). Similar regioselectivityis also possible without the benefit of coordinating functionality bytreatment of 4-chloropyridine with n-butyllithium-tetramethylenediamine(TMEDA) chelate or lithium diisopropylamide (LDA) or similardialkylamide bases. (Queguiner, G. et al J. Heterocyclic Chem 1988, 25,81-87).

Addition of the anion of tert-butyl acetate to the formylated pyridinegave 4-Scheme 4, and acid promoted cyclization/dehydration of 4-Scheme 4afforded 5-chloro[1,8]naphthyridin-2(1H)-one 5-Scheme 4. Condensation ofkinetically generated ester enolates of other esters is also possible.Alternatively alkyl acetoacetate anion may react with the aldehyde3-Scheme 4 to form an aldol addition product which may be cyclized,hydrolyzed and, decarboxylated to afford the desired ring system.

The Suzuki reaction of 5-Scheme 4 with aryl boronic acids using apalladium catalyst, such as, tetrakis(triphenylphosphine)palladium(0)catalyst proceeds to afford 6-Scheme 4. This is a well known reaction,which proceeds efficiently on electron deficient chloro-heterocyclessuch as 5-Scheme 4 (Ali, N M et al Tetrahedron 1992, 48, 8117-8126).Alternatively, the bi-aryl coupling reaction of 5-Scheme 4 can beperformed using aryl or heteroaryl organozinc, organcopper, organotin,or other organometallic reagents known to afford bi-aryl cross-couplingproducts [See for example Solberg, J.; Undheim, K. Acta ChemicaScandinavia 1989, 62-68]. Displacement of the chlorine in 5-Scheme 4 mayalso be achieved with nitrogen nucleophiles.

The final products 7-Scheme 4 were synthesised via a copper acetatemediated arylation of the pyridone nitrogen of 6-Scheme 4 witharylboronic acids as originally described by Lam and Chan (TetrahedronLett 1998, 2941) and extended to pyridones by Mederski and co-workers(Tetrahedron 1999, 12757). More recently Lam and co-workers extendedthese procedures to allow the use of catalytic Cu(OAc)₂ with in situreoxidation of the Cu(OAc)₂ in the presence of oxidizing agents(Tetrahedron Lett. 2001, 3415). In addition to coupling with arylboronicacids, such Cu(OAc)₂ mediated amide arylations may also be effectedusing other organometalloids such as hypervalent diaryliodonium salts,aryl siloxanes, arylbismuths or arylstannanes.

Alternatively the arylation step may be effected using Buchwald'sprocedures for amide arylation with arylbromides, triflates or iodidesin the presence of a suitable palladium catalyst and base (Organic Lett.2000 1101).

This series of 1H-[1,8]Naphthyridin-2-ones may also be prepared asdepicted in Scheme 5 by an alternative method, which permitssubstitution at the napthyridine C-7. Utilizing previously reportedchemistry, the known 5,7-dichloro[1,8]napthyridin-2-ol 1-Scheme 5(Ferrarini, P L et al Eur. J. Med. Chem. 1998, 33, 383-397) isregioselectively displaced with amines to afford 7-amino napthyridines(Ferrarini, P L et al Eur. J. Med. Chem. 1998, 33, 383-397).

The Suzuki reaction of 2-Scheme 5 with aryl boronic acids using apalladium catalyst, such as, tetrakis(triphenylphosphine)palladium(0)catalyst proceeds to afford 3-Scheme 5. This is a well known reaction,which proceeds efficiently on electron deficient chloro-heterocyclessuch as 2-Scheme 5 (Ali, N M et al Tetrahedron 1992, 48, 8117-8126).Alternatively, the bi-aryl coupling reaction of 2-Scheme 5 can beperformed using aryl or heteroaryl organozinc, organcopper, organotin,or other organometallic reagents known to afford bi-aryl cross-couplingproducts [See for example Solberg, J.; Undheim, K. Acta ChemicaScandinavia 1989, 62-68]. Displacement of the chlorine in 2-Scheme 5 mayalso be achieved with nitrogen nucleophiles.

Compound 3-Scheme 5 then reacts via its amide tautomer via a copperacetate mediated arylation of the pyridone nitrogen of 3-Scheme 5 witharylboronic acids as originally described by Lam and Chan (TetrahedronLett 1998, 2941) and extended to pyridones by Mederski and co-workers(Tetrahedron 1999, 12757) This sequence of reactions affords the desired1,8 napthyridinones. More recently Lam and co-workers extended theseprocedures to allow the use of catalytic Cu(OAc)₂ with in situreoxidation of the Cu(OAc)₂ in the presence of oxidizing agents(Tetrahedron Lett 2001, 3415). In addition to coupling with arylboronicacids, such Cu(OAc)₂ mediated amide arylations may also be effectedusing other organometalloids such as hypervalent diaryliodonium salts,aryl siloxanes, arylbismuths or aryistannanes. Y is an optionalsubstituent on the R₁ moiety, and Y′ is an optional substituent on theR₃ moiety as described herein in the specification.

A series of 2(1H)-quinolones are prepared as depicted in Scheme 6. Thestarting material 1-Scheme 6 may be obtained from the commerciallyavailable 1,3-dibromo-5-methoxy-2-methylbenzene by known literatureprocedures, such as those noted in International Publication No. WO02/058695 A1.

The intermediate 4-Scheme 6 was produced by two different procedures. Inthe first procedure, coupling of the bromide 1-Scheme 6 with malonate ormono malonate in the presence of sodium hydride in THF afforded thedesired compound 2-Scheme 6 after the required saponification anddecarboxylation. Other suitable bases, including but are not limited tolithium hydride, potassium hydride, sodium ethoxide, butyl lithium, mayalso be used in an appropriate organic solvent, including but notlimited to DMF, diethyl ether, dioxane and ethanol. The carboxylic acid2-Scheme 6 may be then converted to the corresponding activatedcarboxylate. For example the acid chloride may be prepared, using oxalylchloride or thionyl chloride, or related reagent. The resultingactivated Carboxylate is then coupled with the requisite amine toprovide the amide 4-Scheme 6.

In the second procedure, the bromide 1-Scheme 6 was treated with alkylacetate such as tert-butyl acetate or ethyl acetate in the presence ofsuitable bases, including but not limited to LDA, BuLi, KHMDS, NaHMDS,to provide the desired ester 3-Scheme 6. If the ester is tert-butyl, itmay be cleaved with TFA to the carboxylic acid, which may be convertedto the methyl ester with any one of a number of known methods such aswith trimethylsilyldiazomethane. The ester was then converted to theamide 4-Scheme 6 by treatment with AlMe₃ and the corresponding amine.

The cyclization of the amide 4-Scheme 6 to afford 5-Scheme 6 wascompleted by heating the reaction in DMF with copper(I) iodide andpotassium carbonate. The reaction had fewer impurities and was shortenedin duration if heating was accompanied by microwave irradiation. Othersuitable bases, include but are not limited to lithium hydride, sodiumhydride, potassium hydride, pyridine, maybe used in an appropriateorganic solvent such as DMSO, ethoxyethanol (see for example Boschelli,D. H. et al. J. Med. Chem. 2001, 44, 822). Alternatively, thecyclization reaction may also be performed using a palladium catalystsuch as Pd₂(dba)₃ with the suitable phosphorous ligands, including butnot limited to tri(tert-butyl)phosphine, to (o-biphenyl)P(t-Bu)₂,(o-biphenyl)PCy₂ (See for example Yang, B. H.; Buchwald, S. L. Org. Lett1999, 1, 35-37).

The aryl bromide 5-Scheme 6 was coupled to arylboronic acids underSuzuki coupling conditions, using a palladium catalyst, such astetrakis(triphenylphosphine)-palladium(0), to afford good to excellentyields of 6-Scheme 6. Alternatively, the biaryl coupling reaction of5-Scheme 6 may be performed using aryl or heteroaryl organozinc,organocopper, organotin, or other organometallic reagents known toafford biaryl cross-coupling products such as 6-Scheme 6 (see forexample Solberg, J.; Undheim, K. Acta. Chemica. Scandinavia. 1989, 62).

Oxidation of 6-Scheme 6 to 7-Scheme 6 could be achieved via abromination and elimination process with N-bromosuccinimide and AIBN asreported above for the napthyridinone scaffolds, however, this wasproblematic as a result of concomitant bromination of the quinilonering. Alternatively, oxidative dehydrogenolysis was achieved by treating6-Scheme 6 with MnO₂ without side reactions. This process could also becompleted via an α-oxidation of 6-Scheme 6 using other suitableoxidation reagents such as Davis reagent (Davis, F. A.; Sheppard, A. C.Tetrahedron 1989, 45, 5703), followed by an elimination to provide7-Scheme 6. DDQ is also an effective reagent for this transformation.

The methyl ether 7-Scheme 6 was cleaved using boron tribromide, andtreated with N-phenyltrifluoromethanesulfonimide to give the triflate8-Scheme 6. Other suitable triflating reagents such astrifluoromethanesulfonic anhydride could also be used.

Finally, the triflate 8-Scheme 6 was coupled to aryl amine or alkylamine under amination conditions to give the aryl amine 9-Scheme 6,using palladium complexes supported by phosphine ligands, including butnot limited to (o-biphenyl)P(t-Bu)₂, (o-biphenyl)PCy₂,tri(tert-butyl)phosphine (see Buchwald, S. L. J. Org. Chem. 2000, 65,1158). Alternatively, oxygen nucleophiles could also be used in thecoupling reaction to provide the corresponding aryl ether derivatives(see Hartwig, J. F. Angew. Chem. Int. Ed. 1998, 37, 2046). Ar is anoptionally substituted aryl for the R₃ moiety, and R₄ is as describedherein in the specification.

a, (CF₃SO₂)₂O/CH₂Cl₂/pyridine; b, ArB(OH)₂/(Ph₃P)₄Pd/aq.K₂CO₃/1,4-dioxane; c, mCPBA/CHCl₃; d, tosylchloride/CHCl₃/aq. K₂CO₃; e,4-fluorophenylboronic acid/powdered 4 Å sieves/Cu(OAc)₂/pyridine/Et₃N.

The 5-hydroxyquinoline 1-Scheme 7 was triflated with triflic anhydridein pyridine to afford triflate 2-Scheme 7. Compound 1 or relatedhydroxyquinolines may also be triflated usingN-phenyltrifluoromethanesulfonamide or2-[N,N-bis(trifluoromethylsulfonyl)-amino]-pyridine and relatedtriflating agents. Substitution of the triflate via a palladiumcatalysed Suzuki reaction with an aryl boronic acid afforded the 5-arylquinoline 3. Related transformations may also be effected using othersubstituted quinolin-5-yl halogens or electron deficient sulfonates andcoupling of these with diverse organometallics aided by transition metalcatalysis as recorded in the literature and utilizing catalysts such asPdCl2(PPh3)2 (Perkin I, 2000, 2591) or NiCl₂(PPh₃)₂ (Chem Lett, 2001,976).

N-oxidation with 3-chloroperoxybenzoic acid formed the quinolineN-oxides 4. This transformation may also be achieved using 30% aqueoushydrogen peroxide in acidic acid. Rearrangement using tosyl chlorideunder basic conditions afforded the 5-substituted quinolinone system 5.This well known quinoline N-oxide rearrangement can also be effectedwith acylating agents such as benzoyl chloride or acetic anhydride inthe presence of aqueous base.

The final products, 6-Scheme 7, were synthesised via a copper acetatemediated arylation of the pyridone nitrogen with arylboronic acids asoriginally described by Lam and Chan (Tetrahedron Lett 1998, 2941) andextended to pyridones by Mederski and co-workers (Tetrahedron 1999,12757.) More recently Lam and co-workers extended these procedures toallow the use of catalytic Cu(OAc)₂ with in situ reoxidation of theCu(OAc)₂ in the presence of oxidizing agents (Tetrahedron Lett. 2001,3415.). In addition to coupling with arylboronic acids, such Cu(OAc)₂mediated amide arylations may also be effected using otherorganometalloids such as hypervalent diaryliodonium salts, arylsiloxanes, arylbismuths or arylstannanes.

Alternatively the arylation step may be effected using Buchwald'sprocedures for amide arylation with arylbromides, triflates or iodidesin the presence of a suitable palladium catalyst and base (Organic Lett.2000 1101). Ar=optionally substituted aryl for the R₁ moiety, and Y′ isan optional substituent on the R₃ moiety as described herein in thespecification.

Methods of Treatment

The compounds of Formula (I) and (Ia) or a pharmaceutically acceptablesalt thereof can be used in the manufacture of a medicament for theprophylactic or therapeutic treatment of any disease state in a human,or other mammal, which is exacerbated or caused by excessive orunregulated cytokine production by such mammal's cell, such as but notlimited to monocytes and/or macrophages.

For purposes herein, compounds of Formula (I) and (Ia) will all bereferred to as compounds of Formula (I) unless otherwise indicated.

Compounds of Formula (I) are capable of inhibiting proinflammatorycytokines, such as IL-1, IL-6, IL-8, and TNF and are therefore of use intherapy. IL-1, IL-6, IL-8 and TNF affect a wide variety of cells andtissues and these cytokines, as well as other leukocyte-derivedcytokines, are important and critical inflammatory mediators of a widevariety of disease states and conditions. The inhibition of thesepro-inflammatory cytokines is of benefit in controlling, reducing andalleviating many of these disease states.

Accordingly, the present invention provides a method of treating acytokine-mediated disease which comprises administering an effectivecytokine-interfering amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof.

Compounds of Formula (I) are capable of inhibiting inducibleproinflammatory proteins, such as COX-2, also referred to by many othernames such as prostaglandin endoperoxide synthase-2 (PGHS-2) and aretherefore of use in therapy. These proinflammatory lipid mediators ofthe cyclooxygenase (CO) pathway are produced by the inducible COX-2enzyme. Regulation, therefore of COX-2 which is responsible for thethese products derived from arachidonic acid, such as prostaglandin'saffect a wide variety of cells and tissues are important and criticalinflammatory mediators of a wide variety of disease states andconditions. Expression of COX-1 is not effected by compounds of Formula(I). This selective inhibition of COX-2 may alleviate or spareulcerogenic liability associated with inhibition of COX-1 therebyinhibiting prostoglandins essential for cytoprotective effects. Thusinhibition of these pro-inflammatory mediators is of benefit incontrolling, reducing and alleviating many of these disease states. Mostnotably these inflammatory mediators, in particular prostaglandins, havebeen implicated in pain, such as in the sensitization of pain receptors,or edema. This aspect of pain management therefore includes treatment ofneuromuscular pain, headache, cancer pain, and arthritis pain. Compoundsof Formula (I) or a pharmaceutically acceptable salt thereof, are of usein the prophylaxis or therapy in a human, or other mammal, by inhibitionof the synthesis of the COX-2 enzyme.

Accordingly, the present invention provides a method of inhibiting thesynthesis of COX-2 which comprises administering an effective amount ofa compound of Formula (I) or a pharmaceutically acceptable salt thereof.The present invention also provides for a method of prophylaxistreatment in a human, or other mammal, by inhibition of the synthesis ofthe COX-2 enzyme.

In particular, compounds of Formula (I) or a pharmaceutically acceptablesalt thereof are of use in the prophylaxis or therapy of any diseasestate in a human, or other mammal, which is exacerbated by or caused byexcessive or unregulated IL-1, IL-6, IL-8 or TNF production by suchmammal's cell, such as, but not limited to, monocytes and/ormacrophages.

Accordingly, in another aspect, this invention relates to a method ofinhibiting the production of IL-1 in a mammal in need thereof whichcomprises administering to said mammal an effective amount of a compoundof Formula (I) or a pharmaceutically acceptable salt thereof.

There are many disease states in which excessive or unregulated IL-1production is implicated in exacerbating and/or causing the disease.These include rheumatoid arthritis, osteoarthritis, meningitis, ischemicand hemorrhagic stroke, neurotrauma/closed head injury, stroke,endotoxemia and/or toxic shock syndrome, other acute or chronicinflammatory disease states such as the inflammatory reaction induced byendotoxin or inflammatory bowel disease, tuberculosis, atherosclerosis,muscle degeneration, multiple sclerosis, cachexia, bone resorption,psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis,rubella arthritis and acute synovitis. Recent evidence also links IL-1activity to diabetes, pancreatic β cell diseases and Alzheimer'sdisease.

Use of a CSAID inhibitor compound for the treatment of CSBP mediateddisease states, can include, but not be limited to neurodegenerativediseases, such as Alzheimer's disease (as noted above), Parkinson'sdisease and multiple sclerosis, etc.

In a further aspect, this invention relates to a method of inhibitingthe production of TNF in a mammal in need thereof which comprisesadministering to said mammal an effective amount of a compound ofFormula (I) or a pharmaceutically acceptable salt thereof.

Excessive or unregulated TNF production has been implicated in mediatingor exacerbating a number of diseases including rheumatoid arthritis,rheumatoid spondylitis, osteoarthritis, gouty arthritis and otherarthritic conditions, sepsis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, adult respiratory distresssyndrome, chronic pulmonary inflammatory disease and chronic obstructivepulmonary disease, silicosis, pulmonary sarcoisosis, bone resorptiondiseases, such as osteoporosis, cardiac, brain and renal reperfusioninjury, graft vs. host reaction, allograft rejections, fever andmyalgias due to infection, such as influenza, brain infections includingencephalitis (including HIV-induced forms), cerebral malaria,meningitis, ischemic and hemorrhagic stroke, cachexia secondary toinfection or malignancy, cachexia secondary to acquired immunedeficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloidformation, scar tissue formation, inflammatory bowel disease, Crohn'sdisease, ulcerative colitis and pyresis.

Compounds of Formula (I) are also useful in the treatment of viralinfections, where such viruses are sensitive to upregulation by TNF orwill elicit TNF production in vivo. The viruses contemplated fortreatment herein are those that produce TNF as a result of infection, orthose which are sensitive to inhibition, such as by decreasedreplication, directly or indirectly, by the TNF inhibiting-compounds ofFormula (1). Such viruses include, but are not limited to HIV-1, HIV-2and HIV-3, Cytomegalovirus (CMV), Influenza, adenovirus and the Herpesgroup of viruses, such as but not limited to, Herpes Zoster and HerpesSimplex. Accordingly, in a further aspect, this invention relates to amethod of treating a mammal afflicted with a human immunodeficiencyvirus (HIV) which comprises administering to such mammal an effectiveTNF inhibiting amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof.

It is also recognized that both IL-6 and IL-8 are produced duringrhinovirus (HRV) infections and contribute to the pathogenesis of commoncold and exacerbation of asthma associated with HRV infection (Turner etal. (1998), Clin. Infec. Dis., Vol 26, p 840; Teren et al. (1997), Am JRespir Crit Care Med vol 155, p 1362; Grunberg et al. (1997), Am JRespir Crit Care Med 156:609 and Zhu et al, J Clin Invest (1996),97:421). It has also been demonstrated in vitro that infection ofpulmonary epithelial cells with HRV results in production of IL-6 andIL-8 (Subauste et al., J. Clin. Invest. 1995, 96:549.) Epithelial cellsrepresent the primary site of infection of HRV. Therefore another aspectof the present invention is a method of treatment to reduce inflammationassociated with a rhinovirus infection, not necessarily a direct effecton virus itself.

Compounds of Formula (I) may also be used in association with theveterinary treatment of mammals, other than in humans, in need ofinhibition of TNF production. TNF mediated diseases for treatment,therapeutically or prophylactically, in animals include disease statessuch as those noted above, but in particular viral infections. Examplesof such viruses include, but are not limited to, lentivirus infectionssuch as, equine infectious anaemia virus, caprine arthritis virus, visnavirus, or maedi virus or retrovirus infections, such as but not limitedto feline immunodeficiency virus (FIV), bovine immunodeficiency virus,or canine immunodeficiency virus or other retroviral infections.

The compounds of Formula (I) may also be used topically in the treatmentor prophylaxis of topical disease states mediated by or exacerbated byexcessive cytokine production, such as by IL-1 or TNF respectively, suchas inflamed joints, eczema, psoriasis and other inflammatory skinconditions such as sunburn; inflammatory eye conditions includingconjunctivitis; pyresis, pain and other conditions associated withinflammation. Periodontal disease has also been implemented in cytokineproduction, both topically and systemically. Hence use of compounds ofFormula (I) to control the inflammation associated with cytokineproduction in such peroral diseases such as gingivitis and periodontitisis another aspect of the present invention.

Compounds of Formula (I) have also been shown to inhibit the productionof IL-8 (Interleukin-8, NAP). Accordingly, in a further aspect, thisinvention relates to a method of inhibiting the production of IL-8 in amammal in need thereof which comprises administering to said mammal aneffective amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof.

There are many disease states in which excessive or unregulated IL-8production is implicated in exacerbating and/or causing the disease.These diseases are characterized by massive neutrophil infiltration suchas, psoriasis, inflammatory bowel disease, asthma, cardiac, brain andrenal reperfusion injury, adult respiratory distress syndrome,thrombosis and glomerulonephritis. All of these diseases are associatedwith increased IL-8 production which is responsible for the chemotaxisof neutrophils into the inflammatory site. In contrast to otherinflammatory cytokines (IL-1, TNF, and IL-6), IL-8 has the uniqueproperty of promoting neutrophil chemotaxis and activation. Therefore;the inhibition of IL-8 production would lead to a direct reduction inthe neutrophil infiltration.

The compounds of Formula (I) are administered in an amount sufficient toinhibit cytokine, in particular IL-1, IL-6, IL-8 or TNF, production suchthat it is regulated down to normal levels, or in some case to subnormallevels, so as to ameliorate or prevent the disease state. Abnormallevels of IL-1, IL-6, IL-8 or TNF, for instance in the context of thepresent invention, constitute: (i) levels of free (not cell bound) IL-1,IL-6, IL-8 or TNF greater than or equal to 1 picogram per ml; (ii) anycell associated IL-1, IL-6, IL-8 or TNF; or (iii) the presence of IL-1,IL-6, IL-8 or TNF mRNA above basal levels in cells or tissues in whichIL-1, IL-6, IL-8 or TNF, respectively, is produced.

The discovery that the compounds of Formula (I) are inhibitors ofcytokines, specifically IL-1, IL-6, IL-8 and TNF is based upon theeffects of the compounds of Formulas (I) on the production of the IL-1,IL-8 and TNF in in vitro assays which are described herein.

As used herein, the term “inhibiting the production of IL-1 (IL-6, IL-8or TNF)” refers to:

a) a decrease of excessive in vivo levels of the cytokine (IL-1, IL-6,IL-8 or TNF) in a human to normal or sub-normal levels by inhibition ofthe in release of the cytokine by all cells, including but not limitedto monocytes or macrophages;

b) a down regulation, at the genomic level, of excessive in vivo levelsof the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal orsub-normal levels;

c) a down regulation, by inhibition of the direct synthesis of thecytokine (IL-1, IL-6, IL-8 or TNF) as a postranslational event; or

d) a down regulation, at the translational level, of excessive in vivolevels of the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal orsub-normal levels.

As used herein, the term “TNF mediated disease or disease state” refersto any and all disease states in which TNF plays a role, either byproduction of TNF itself, or by TNF causing another monokine to bereleased, such as but not limited to IL-1, IL-6 or IL-8. A disease statein which, for instance, IL-1 is a major component, and whose productionor action, is exacerbated or secreted in response to TNF, wouldtherefore be considered a disease stated mediated by TNF.

As used herein, the term “cytokine” refers to any secreted polypeptidethat affects the functions of cells and is a molecule which modulatesinteractions between cells in the immune, inflammatory or hematopoieticresponse. A cytokine includes, but is not limited to, monokines andlymphokines, regardless of which cells produce them. For instance, amonokine is generally referred to as being produced and secreted by amononuclear cell, such as a macrophage and/or monocyte. Many other cellshowever also produce monokines, such as natural killer cells,fibroblasts, basophils, neutrophils, endothelial cells, brainastrocytes, bone marrow stromal cells, epideral keratinocytes andB-lymphocytes. Lymphokines are generally referred to as being producedby lymphocyte cells. Examples of cytokines include, but are not limitedto, Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8),Tumor Necrosis Factor-alpha (TNF-a) and Tumor Necrosis Factor beta(TNF-β).

As used herein, the term “cytokine interfering” or “cytokine suppressiveamount” refers to an effective amount of a compound of Formula (I) whichwill cause a decrease in the in vivo levels of the cytokine to normal orsub-normal levels, when given to a patient for the prophylaxis ortreatment of a disease state which is exacerbated by, or caused by,excessive or unregulated cytokine production.

As used herein, the cytokine referred to in the phrase “inhibition of acytokine, for use in the treatment of a HIV-infected human” is acytokine which is implicated in (a) the initiation and/or maintenance ofT cell activation and/or activated T cell-mediated HIV gene expressionand/or replication and/or (b) any cytokine-mediated disease associatedproblem such as cachexia or muscle degeneration.

As TNF-β (also known as lymphotoxin) has close structural homology withTNF-□ (also known as cachectin) and since each induces similar biologicresponses and binds to the same cellular receptor, both TNF-α and TNF-βare inhibited by the compounds of the present invention and thus areherein referred to collectively as “TNF” unless specifically delineatedotherwise.

A member of the MAP kinase family, alternatively termed CSBP, p38, orRK, has been identified independently by several laboratories.Activation of this novel protein kinase via dual phosphorylation hasbeen observed in different cell systems upon stimulation by a widespectrum of stimuli, such as physicochemical stress and treatment withlipopolysaccharide or proinflammatory cytokines such as interleukin-1and tumor necrosis factor. The cytokine biosynthesis inhibitors, of thepresent invention, compounds of Formula (I) have been determined to bepotent and selective inhibitors of CSBP/p38/RK kinase activity. Theseinhibitors are of aid in determining the signaling pathways involvementin inflammatory responses. In particular, for the first time adefinitive signal transduction pathway can be prescribed to the actionof lipopolysaccharide in cytokine production in macrophages. In additionto those diseases already noted, treatment of stroke, neurotrauma,cardiac and renal reperfusion injury, congestive heart failure, coronaryarterial bypass grafting (CABG) surgery, chronic renal failure,angiogenesis & related processes, such as cancer, thrombosis,glomerulonephritis, diabetes and pancreatic □ cells, multiple sclerosis,muscle degeneration, eczema, psoriasis, sunburn, and conjunctivitis arealso included.

The CSBP inhibitors were subsequently tested in a number of animalmodels for anti-inflammatory activity. Model systems were chosen thatwere relatively insensitive to cyclooxygenase inhibitors in order toreveal the unique activities of cytokine suppressive agents. Theinhibitors exhibited significant activity in many such in vivo studies.Most notable are its effectiveness in the collagen-induced arthritismodel and inhibition of TNF production in the endotoxic shock model. Inthe latter study, the reduction in plasma level of TNF correlated withsurvival and protection from endotoxic shock related mortality. Also ofgreat importance are the compounds effectiveness in inhibiting boneresorption in a rat fetal long bone organ culture system. Griswold etal., (1988) Arthritis Rheum. 31:1406-1412; Badger, et al., (1989) Circ.Shock 27, 51-61; Votta et al., (1994) in vitro. Bone 15, 533-538; Lee etal., (1993). B Ann. N.Y. Acad. Sci. 696, 149-170.

Chronic diseases which have an inappropriate angiogenic component arevarious

ocular neovasularizations, such as diabetic retinopathy and maculardegeneration. Other chronic diseases which have an excessive orincreased proliferation of vasculature are tumor growth and metastasis,atherosclerosis, and certain arthritic conditions. Therefore CSBP kinaseinhibitors will be of utility in the blocking of the angiogeniccomponent of these disease states.

The term “excessive or increased proliferation of vasculatureinappropriate angiogenesis” as used herein includes, but is not limitedto, diseases which are characterized by hemangiomas and ocular diseases.

The term “inappropriate angiogenesis” as used herein includes, but isnot limited to, diseases which are characterized by vesicleproliferation with accompanying tissue proliferation, such as occurs incancer, metastasis, arthritis and atherosclerosis.

Accordingly, the present invention provides a method of treating a CSBPkinase mediated disease in a mammal in need thereof, preferably a human,which comprises administering to said mammal, an effective amount of acompound of Formula (I) or a pharmaceutically acceptable salt thereof.

In order to use a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof in therapy, it will normally be formulated intoa pharmaceutical composition in accordance with standard pharmaceuticalpractice. This invention, therefore, also relates to a pharmaceuticalcomposition comprising an effective, non-toxic amount of a compound ofFormula (I) and a pharmaceutically acceptable carrier or diluent.

Compounds of Formula (I), pharmaceutically acceptable salts thereof andpharmaceutical compositions incorporating such may conveniently beadministered by any of the routes conventionally used for drugadministration, for instance, orally, topically, parenterally or byinhalation. The compounds of Formula (I) may be administered inconventional dosage forms prepared by combining a compound of Formula(I) with standard pharmaceutical carriers according to conventionalprocedures.

The compounds of Formula (I) may also be administered in conventionaldosages in combination with a known, second therapeutically activecompound. These procedures may involve mixing, granulating andcompressing or dissolving the ingredients as appropriate to the desiredpreparation. It will be appreciated that the form and character of thepharmaceutically acceptable character or diluent is dictated by theamount of active ingredient with which it is to be combined, the routeof administration and other well-known variables. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Exemplary of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acidand the like. Exemplary of liquid carriers are syrup, peanut oil, oliveoil, water and the like. Similarly, the carrier or diluent may includetime delay material well known to the art, such as glycerylmono-stearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg. to about 1 g. When a liquid carrier is used,the preparation will be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as an ampoule or nonaqueousliquid suspension.

Compounds of Formula (I) may be administered topically, that is bynon-systemic administration. This includes the application of a compoundof Formula (I) externally to the epidermis or the buccal cavity and theinstillation of such a compound into the ear, eye and nose, such thatthe compound does not significantly enter the blood stream. In contrast,systemic administration refers to oral, intravenous, intraperitoneal andintramuscular administration.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin tothe site of inflammation such as liniments, lotions, creams, ointmentsor pastes, and drops suitable for administration to the eye, ear ornose. The active ingredient may comprise, for topical administration,from 0.001% to 10% w/w, for instance from 1% to 2% by weight of theformulation. It may however comprise as much as 10% w/w but preferablywill comprise less than 5% w/w, more preferably from 0.1% to 1% w/w ofthe formulation.

Lotions according to the present invention include those suitable forapplication to the skin or eye. An eye lotion may comprise a sterileaqueous solution optionally containing a bactericide and may be preparedby methods similar to those for the preparation of drops. Lotions orliniments for application to the skin may also include an agent tohasten drying and to cool the skin, such as an alcohol or acetone,and/or a moisturizer such as glycerol or an oil such as castor oil orarachis oil.

Creams, ointments or pastes according to the present invention aresemi-solid formulations of the active ingredient for externalapplication. They may be made by mixing the active ingredient infinely-divided or powdered form, alone or in solution or suspension inan aqueous or non-aqueous fluid, with the aid of suitable machinery,with a greasy or non-greasy base. The base may comprise hydrocarbonssuch as hard, soft or liquid paraffin, glycerol, beeswax, a metallicsoap; a mucilage; an oil of natural origin such as almond, corn,arachis, castor or olive oil; wool fat or its derivatives or a fattyacid such as stearic or oleic acid together with an alcohol such aspropylene glycol or a macrogel. The formulation may incorporate anysuitable surface active agent such as an anionic, cationic or non-ionicsurfactant such as a sorbitan ester or a polyoxyethylene derivativethereof. Suspending agents such as natural gums, cellulose derivativesor inorganic materials such as siliceous silicas, and other ingredientssuch as lanolin, may also be included.

Drops according to the present invention may comprise sterile aqueous oroily solutions or suspensions and may be prepared by dissolving theactive ingredient in a suitable aqueous solution of a bactericidaland/or fungicidal agent and/or any other suitable preservative, andpreferably including a surface active agent. The resulting solution maythen be clarified by filtration, transferred to a suitable containerwhich is then sealed and sterilized by autoclaving or maintaining at98-100° C. for half an hour. Alternatively, the solution may besterilized by filtration and transferred to the container by an aseptictechnique. Examples of bactericidal and fungicidal agents suitable forinclusion in the drops are phenylmercuric nitrate or acetate (0.002%),benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).Suitable solvents for the preparation of an oily solution includeglycerol, diluted alcohol and propylene glycol.

Compounds of Formula (I) may be administered parenterally, that is byintravenous, intramuscular, subcutaneous intranasal, intrarectal,intravaginal or intraperitoneal administration. The subcutaneous andintramuscular forms of parenteral administration are generallypreferred. Appropriate dosage forms for such administration may beprepared by conventional techniques. Compounds of Formula (I) may alsobe administered by inhalation, that is by intranasal and oral inhalationadministration. Appropriate dosage forms for such administration, suchas an aerosol formulation or a metered dose inhaler, may be prepared byconventional techniques.

For all methods of use disclosed herein for the compounds of Formula(I), the daily oral dosage regimen will preferably be from about 0.1 toabout 80 mg/kg of total body weight, preferably from about 0.2 to 30mg/kg, more preferably from about 0.5 mg to 15 mg. The daily parenteraldosage regimen about 0.1 to about 80 mg/kg of total body weight,preferably from about 0.2 to about 30 mg/kg, and more preferably fromabout 0.5 mg to 15 mg/kg. The daily topical dosage regimen willpreferably be from 0.1 mg to 150 mg, administered one to four,preferably two or three times daily. The daily inhalation dosage regimenwill preferably be from about 0.01 mg/kg to about 1 mg/kg per day. Itwill also be recognized by one of skill in the art that the optimalquantity and spacing of individual dosages of a compound of Formula (I)or a pharmaceutically acceptable salt thereof will be determined by thenature and extent of the condition being treated, the form, route andsite of administration, and the particular patient being treated, andthat such optimums can be determined by conventional techniques. It willalso be appreciated by one of skill in the art that the optimal courseof treatment, i.e., the number of doses of a compound of Formula (I) ora pharmaceutically acceptable salt thereof given per day for a definednumber of days, can be ascertained by those skilled in the art usingconventional course of treatment determination tests.

The novel compounds of Formula (I) may also be used in association withthe veterinary treatment of mammals, other than humans, in need ofinhibition of CSBP/p38 or cytokine inhibition or production. Inparticular, CSBP/p38 mediated diseases for treatment, therapeutically orprophylactically, in animals include disease states such as those notedherein in the Methods of Treatment section, but in particular viralinfections. Examples of such viruses include, but are not limited to,lentivirus infections such as, equine infectious anaemia virus, caprinearthritis virus, visna virus, or maedi virus or retrovirus infections,such as but not limited to feline immunodeficiency virus (FIV), bovineimmunodeficiency virus, or canine immunodeficiency virus or otherretroviral infections.

Another aspect of the present invention is a method of treating thecommon cold or respiratory viral infection caused by human rhinovirus(HRV), other enteroviruses, coronavirus, influenza virus, parainfluenzavirus, respiratory syncytial virus, or adenovirus in a human in needthereof which method comprises administering to said human an effectiveamount of a CBSP/p38 inhibitor.

Another aspect of the present invention is a method of treating,including prophylaxis of influenza induced pneumonia in a human in needthereof which method comprises administering to said human an effectiveamount of a CBSP/p38 inhibitor

The present invention also relates to the use of the CSBP/p38 kinaseinhibitor for the treatment, including prophylaxis, of inflammationassociated with a viral infection of a human rhinovirus (HRV), otherenteroviruses, coronavirus, influenza virus, parainfluenza virus,respiratory syncytial virus, or adenovirus.

In particular, the present invention is directed to the treatment of aviral infection in a human, which is caused by the human rhinovirus(HRV), other enterovirus, coronavirus, influenza virus, parainfluenzavirus, respiratory syncytial virus, or an adenovirus. In particular theinvention is directed to respiratory viral infections that exacerbateasthma (induced by such infections), chronic bronchitis, chronicobstructive pulmonary disease, otitis media, and sinusitis. Whileinhibiting IL-8 or other cytokines may be beneficial in treating arhinovirus may be known, the use of an inhibitor of the p38 kinase fortreating HRV or other respiratory viral infections causing the commoncold is believed novel. It should be noted that the respiratory viralinfection treated herein might also be associated with a secondarybacterial infection, such as otitis media, sinusitis, or pneumonia.

For use herein treatment may include prophylaxis for use in a treatmentgroup susceptible to such infections. It may also include reducing thesymptoms of, ameliorating the symptoms of, reducing the severity of,reducing the incidence of, or any other change in the condition of thepatient, which improves the therapeutic outcome.

It should be noted that the treatment herein is not directed to theelimination or treatment of the viral organism itself but is directed totreatment of the respiratory viral infection that exacerbates otherdiseases or symptoms of disease, such as asthma (induced by suchinfections), chronic bronchitis, chronic obstructive pulmonary disease,otitis media, and sinusitis.

A preferred virus for treatment herein is the human rhinovirus infection(HRV) or respiratory syncytial virus (RSV).

The invention will now be described by reference to the followingbiological examples that are merely illustrative and are not to beconstrued as a limitation of the scope of the present invention.

BIOLOGICAL EXAMPLES

The cytokine-inhibiting effects of compounds of the present inventionmay be determined by the following in vitro assays: Assays forInterleukin-1 (IL-1), Interleukin-8

(IL-8), and Tumour Necrosis Factor (TNF) are well known in the art, andmay be found in a number of publications, and patents. Representativesuitable assays for use herein are described in Adams et al., U.S. Pat.No. 5,593,992, whose disclosure is incorporated by reference in itsentirety.

Interleukin-1 (IL-1)

Human peripheral blood monocytes are isolated and purified from eitherfresh blood preparations from volunteer donors, or from blood bank buffycoats, according to the procedure of Colotta et al, J Immunol, 132, 936(1984). These monocytes (1×10⁶) are plated in 24-well plates at aconcentration of 1-2 million/ml per well. The cells are allowed toadhere for 2 hours, after which time non-adherent cells are removed bygentle washing. Test compounds are then added to the cells for 1 hbefore the addition of lipopolysaccharide (50 ng/ml), and the culturesare incubated at 37° C. for an additional 24 h. At the end of thisperiod, culture supernatants are removed and clarified of cells and alldebris. Culture supernatants are then immediately assayed for IL-1biological activity, either by the method of Simon et al., J. Immunol.Methods, 84, 85, (1985) (based on ability of IL-1 to stimulate aInterleukin 2 producing cell line (EL-4) to secrete IL-2, in concertwith A23187 ionophore) or the method of Lee et al., J. ImmunoTherapy, 6(1), 1-12 (1990) (ELISA assay).

In Vivo TNF Assay:

-   (1) Griswold et al., Drugs Under Exp. and Clinical Res., XIX (6),    243-248 (1993); or-   (2) Boehm, et al., Journal Of Medicinal Chemistry 39,    3929-3937 (1996) whose disclosures    are incorporated by reference herein in their entirety.    LPS-Induced TNFα Production in Mice and Rats

In order to evaluate in vivo inhibition of LPS-induced TNFα productionin rodents, both mice and rats are injected with LPS.

Mouse Method

Male Balb/c mice from Charles River Laboratories are pretreated (30minutes) with compound or vehicle. After the 30 min. pretreat time, themice are given LPS (lipopolysaccharide from Esherichia coil Serotype055-85, Sigma Chemical Co., St Louis, Mo.) 25 ug/mouse in 25 ulphosphate buffered saline (pH 7.0) intraperitoneally. Two hours laterthe mice are killed by CO₂ inhalation and blood samples are collected byexsanguination into heparinized blood collection tubes and stored onice. The blood samples are centrifuged and the plasma collected andstored at −20° C. until assayed for TNFα by ELISA.

Rat Method

Male Lewis rats from Charles River Laboratories are pretreated atvarious times with compound or vehicle. After a determined pretreattime, the rats are given LPS (lipopolysaccharide from Esherichia coliSerotype 055-85, Sigma Chemical Co., St Louis, Mo.) 3.0 mg/kgintraperitoneally. The rats are killed by CO₂ inhalation and heparinizedwhole blood is collected from each rat by cardiac puncture 90 minutesafter the LPS injection. The blood samples are centrifuged and theplasma collected for analysis by ELISA for TNFα levels.

ELISA Method

TNFα levels were measured using a sandwich ELISA, as described inOlivera et al., Circ. Shock, 37, 301-306, (1992), whose disclosure isincorporated by reference in its entirety herein, using a hamstermonoclonal antimurine TNFα (Genzyme, Boston, Mass.) as the captureantibody and a polyclonal rabbit antimurine TNFa (Genzyme) as the secondantibody. For detection, a peroxidase-conjugated goat antirabbitantibody (Pierce, Rockford, Ill.) was added, followed by a substrate forperoxidase (1 mg/ml orthophenylenediamine with 1% urea peroxide). TNFαlevels in the plasma samples from each animal were calculated from astandard curve generated with recombinant murine TNFα (Genzyme).

LPS-Stimulated Cytokine Production in Human Whole Blood

Assay: Test compound concentrations were prepared at 10× concentrationsand LPS prepared at 1 ug/ml (final conc. of 50 ng/ml LPS) and added in50 uL volumes to 1.5 mL eppendorf tubes. Heparinized human whole bloodwas obtained from healthy volunteers and was dispensed into eppendorftubes containing compounds and LPS in 0.4 mL volumes and the tubesincubated at 37 C. Following a 4 hour incubation, the tubes werecentrifuged at 5000 rpm for 5 minutes in a TOMY microfuge, plasma waswithdrawn and frozen at −80 C.

Cytokine measurement: IL-I and/or TNF were quantified using astandardized ELISA technology. An in-house ELISA kit was used to detecthuman IL-1 and TNF. Concentrations of IL-1 or TNF were determined fromstandard curves of the appropriate cytokine and IC50 values for testcompound (concentration that inhibited 50% of LPS-stimulated cytokineproduction) were calculated by linear regression analysis.

CSBP/p38 Kinase Assay:

This assay measures the CSBP/p38-catalyzed transfer of ³²P from[a-³²P]ATP to threonine residue in an epidermal growth factor receptor(EGFR)-derived peptide (T669) with the following sequence:KRELVEPLTPSGEAPNQALLR (residues 661-681). (See Gallagher et al.,“Regulation of Stress Induced Cytokine Production by PyridinylImidazoles: Inhibition of CSBP Kinase”, BioOrganic & MedicinalChemistry, 1997, 5, 49-64).

Reactions are carried in round bottom 96 well plate (from Corning) in a30 ml volume. Reactions contain (in final concentration): 25 mM Hepes,pH 7.5; 8 mM MgCl₂; 0.17 mM ATP (the Km_([ATP]) of p38 (see Lee et al.,Nature 300, n72 pg. 639-746 (December 1994)); 2.5 uCi of [g-32P]ATP; 0.2mM sodium orthovanadate; 1 mM DTT; 0.1% BSA; 10% glycerol; 0.67 mM T669peptide; and 2-4 nM of yeast-expressed, activated and purified p38.Reactions are initiated by the addition of [gamma-32P]Mg/ATP, andincubated for 25 min. at 37° C. Inhibitors (dissolved in DMSO) areincubated with the reaction mixture on ice for 30 minutes prior toadding the 32P-ATP. Final DMSO concentration was 0.16%. Reactions areterminated by adding 10 ul of 0.3 M phosphoric acid, and phosphorylatedpeptide was isolated from the reactions by capturing it on p81phosphocellulose filters. Filters are washed with 75 mM phosphoricacids, and incorporated 32P was quantified using beta scintillationcounter. Under these conditions, the specific activity of p38 will bedetermined and is generally 400-450 pmol/pmol enzyme, and the activitybeing linear for up to 2 hours of incubation. The kinase activity valuesare obtained after subtracting values generated in the absence ofsubstrate which were 10-15% of total values.

Examples 11 and 12 demonstrated significantly less activity in thisassay in comparison to Examples 9 and 10, however they are deemed to beactive inhibitors within the context of this invention. For example, thecompound of Example 9 demonstrated an IC50 in uM of 0.06; Example 10demonstrated an IC50 of 0.2 uM; Example 11 an IC50 of 5 uM and Example12 an IC50 of 13.35.

TNF-α in Traumatic Brain Injury Assay

This assay provides for examination of the expression of tumor necrosisfactor mRNA in specific brain regions, which follow experimentally,induced lateral fluid-percussion traumatic brain injury (TBI) in rats.Since TNF-α is able to induce nerve growth factor (NGF) and stimulatethe release of other cytokines from activated astrocytes, thispost-traumatic alteration in gene expression of TNF-α plays an importantrole in both the acute and regenerative response to CNS trauma. Asuitable assay may be found in WO 97/35856 whose disclosure isincorporated herein by reference.

CNS Injury Model for IL-1β mRNA

This assay characterizes the regional expression of interleukin-1β(IL-1β) mRNA in specific brain regions following experimental lateralfluid-percussion traumatic brain injury (TBI) in rats. Results fromthese assays indicate that following TBI, the temporal expression ofIL-1β mRNA is regionally stimulated in specific brain regions. Theseregional changes in cytokines, such as IL-1β play a role in thepost-traumatic pathologic or regenerative sequelae of brain injury. Asuitable assay may be found in WO 97/35856 whose disclosure isincorporated herein by reference.

Angiogenesis Assay:

Described in WO 97/32583, whose disclosure is incorporated herein byreference, is an assay for determination of inflammatory angiogenesisthat may be used to show that cytokine inhibition will stop the tissuedestruction of excessive or inappropriate proliferation of bloodvessels.

Rhinovirus/Influenza Assay:

Cell lines, rhinovirus serotype 39, and influenza virus A/PR/8/34 werepurchased from American Type Culture Collection (ATCC). BEAS-2B cellswere cultured according to instructions provided by ATCC using BEGM(bronchial epithelial growth media) purchased from Clonetics Corp. HELAcell cultures, used for detection and titration of virus, weremaintained in Eagle's minimum essential media containing 10% fetal calfserum, 2 mM l-glutamine, and 10 mM HEPES buffer (MEM).

A modification of the method reported by Subauste et al., Supra, for invitro infection of human bronchial epithelial cells with rhinovirus wasused in these studies. BEAS-2B cells (2×10⁵/well) were cultured incollagen-coated wells for 24 hours prior to infection with rhinovirus.Rhinovirus serotype 39 was added to cell cultures for one hourincubation at 34° C. after which inoculum was replaced with fresh mediaand cultures were incubated for an additional 72 hours at 34° C.Supernatants collected at 72 hours post-infection were assayed forcytokine protein concentration by ELISA using commercially availablekits (R&D Systems). Virus yield was also determined from culturesupernatants using a microtitration assay in HELA cell cultures(Subauste et al., supra 1995). In cultures treated with p38 kinaseinhibitors, drug was added 30 minutes prior to infection. Stocks ofcompounds were prepared in DMSO (10 mM drug) and stored at −20° C.

For detection of p38 kinase, cultures were incubated in basal mediawithout growth factors and additives to reduce endogenous levels ofactivated p38 kinase. Cells were harvested at various timepoints afteraddition of rhinovirus. Detection of tyrosine phosphorylated p38 kinaseby immunoblot was analyzed by a commercially available kit and wasperformed according to the manufacturer's instructions (PhosphoPlus p38MAPK Antibody Kit: New England BioLabs Inc.).

In some experiments, BEAS-2B cells were infected with influenza virus(strain A/PR/8/34) in place of rhinovirus. Culture supernatant washarvested 48 and 72 hour post-infection and tested by ELISA for cytokineas described above.

Cells and Virus: Influenza A/PR/8/34 sub type Hi Ni (VR-95 American TypeCulture Collection, Roclville, Md.) was grown in the allantoic cavity of10 day old chicken eggs. Following incubation at 37° C., andrefrigeration for 2½ hours at 4° C., allantoic fluid was harvested,pooled, and centrifuged (1,000 rcf; 15 min; 4° C.) to remove cells.Supernatant was aliquoted and stored at −70° C. The titer of the stockculture of virus was 1.0×10¹⁰ Tissue Culture Infective Dose/ml (TCID₅₀)

Inoculation procedure: Four-six week old female Balb/cAnNcrlBr mice wereobtained from Charles River, Raleigh, N.C. Animals were infectedintranasally. Mice were anesthetized by intraperitoneal injection ofKetamine (40 mg/kg; Fort Dodge Labs, Fort Dodge, Iowa) and Xylazine (5mg/kg; Miles, Shawnee Mission, Kans.) and then inoculated with 100TCID50 of PR8 diluted in PBS in 20 ul. Animals were observed daily forsigns of infection. All animal studies were approved by SmithKlineBeecham Pharmaceuticals Institutional Animal Care and Use Committee.

Virus titration: At various times post infection, animals weresacrificed and lungs were aseptically harvested. Tissues werehomogenized, in vials containing 1 micron glass beads (Biospec Products,Bartlesville, Okla.) and 1 ml. of Eagles minimal essential medium. Celldebris was cleared by centrifugation at 1,000 rcf for 15 minutes at 4°C., nd supernatants were serially diluted on Madin-Darby canine kidney(MDCK) cells. After 5 days of incubation at 37° C. (5% CO₂), 50 [d of0.5% chick red blood cells were added per well, and agglutination wasread after 1 hour at room temperature. The virus titer is expressed as50% tissue culture infective dose (TCID₅₀) calculated by logisticregression.

ELISA: Cytokine levels were measured by quantitative ELISA usingcommercially available kits. Ear samples were homogenized using a tissueminser in PBS. Cell debris was cleared by centrifugation at 14,000 rpmfor 5 minutes. The cytokine concentrations and thresholds weredetermined as described by the manufacturer; IL-6, IFN-γ, and KC (R&DSystems, Minneapolis, Minn.).

Myeloperoxidase Assay: Myeloperoxidase (MPO) activity was determinedkinetically as described by Bradley et al. (1982). Briefly, rabbitcornea were homogenized in Hexadecyl Trimethyl-Ammonium Bromide (HTAB)(Sigma Chemical Co. St. Louis, Mo.) which was dissolved in 0.5 mPotassium phosphate buffer (J.T. Baker Scientific, Phillipsburg, N.J.).Following homogenization, the samples were subjected tofreeze-thaw-sonication (Cole-Parmer 8853, Cole-Parmer, Vernon Hills, II)3 times. Suspensions were then cleared by centrifugation at 12,500×g for15 minutes at 4° C. MPO enzymatic activity was determined by colormetricchange in absorbance during a reaction of O-Dianisidine dihydrochloride(ODI) 0.175 mg/ml (Sigma Chemical Co. St. Louis, Mo.) with 0.0002%Hydrogen peroxide (Sigma Chemical Co. St. Louis, Mo.). Measurements wereperformed by using a Beckman Du 640 Spectrophotometer (Fullerton,Calif.) fitted with a temperature control device. 50 ul of material tobe assayed was added to 950 ul of ODI and change in absorbance wasmeasured at a wave length of 460 nm for 2 minutes at 25° C.

Whole Body Plethysomography: Influenza virus infected mice were placedinto a whole body plethysomograph box with an internal volume ofapproximately 350-ml. A bias airflow of one l/min was applied to the boxand flow changes were measured and recorded with a Buxco XA dataacquisition and respiratory analysis system (Buxco Electronics, Sharon,Conn.). Animals were allowed to acclimate to the plethysomograph box for2 min. before airflow data was recorded. Airway measurements werecalculated as Penh (enhanced pause). Penh has previously been shown asan index of airway obstruction and correlates with increasedintrapleural pressure. The algorithm for Penh calculation is as follows:Penh=[(expiratory time/relaxation time)-1]×(peak expiratory flow/peakinspiratory flow) where relaxation time is the amount of time requiredfor 70% of the tidal volume to be expired.

Determination of arterial oxygen saturation. A Nonin veterinary handheld pulse oximeter 8500V with lingual sensor (Nonin Medical, Inc.,Plymouth Minn.) was used to determine daily arterial oxygen saturation %SpO2 as described (Sidwell et al. 1992 Antimicrobial Agents andChemotherapy 36:473-476).

Additional data and assay modifications may be found in PCT/US00/25386,(WO 01/19322) filed 15 Sep. 2000, whose disclosure is incorporatedherein by reference in its entirety.

Fluorescence Anisotropy Kinase Binding Assay

The CSBP kinase enzyme, a fluorescent ligand and a variableconcentration of the test compound are incubated together to reachthermodynamic equilibrium under conditions such that in the absence oftest compound the fluorescent ligand is significantly (>50%) enzymebound and in the presence of a sufficient concentration (>10×K_(i)) of apotent inhibitor the anisotropy of the unbound fluorescent ligand ismeasurably different from the bound value.

The concentration of kinase enzyme should preferably be ≧1×K_(f). Theconcentration of fluorescent ligand required will depend on theinstrumentation used, and the fluorescent and physicochemicalproperties. The concentration used must be lower than the concentrationof kinase enzyme, and preferably less than half the kinase enzymeconcentration.

A typical protocol is:

All components dissolved in Buffer of final composition 62.5 mM HEPES,pH 7.5, 1.25 mM CHAPS, 1.25 mM DUT, 12.5 mM MgCl₂ 3.3% DMSO.

p38 Enzyme concentration: 12 nM

Fluorescent ligand concentration: 5 nM

Test compound concentration: 0.1 nM-100 uM

Components incubated in 30 ul final volume in NUNC 384 well blackmicrotitre plate until equilibrium reached (5-30 mins)

Fluorescence anisotropy read in LJL Acquest.

Definitions:

-   -   K_(i)=dissociation constant for inhibitor binding    -   K_(f)=dissociation constant for fluorescent ligand binding        The fluorescent ligand is the following compound:        which is derived from        5-[2-(4-aminomethylphenyl)-5-pyridin-4-yl-1H-imidazol-4-yl]-2-chlorophenol        and rhodamine green.

Representative compounds of Formula (I) and (Ia) were tested in thisassay. Examples 3 to 7 demonstrated a pKi between 7.8 and 8.8. pKi inthis assay is the negative log of the Ki term as determined herein.

Examples 12 to 14, and 18 to 20 all demonstrated positive IC50's in thisassay, and all are less than 1 micromolar in activity. Examples 2, 8, 9,15(g), Example 17 as two conformational isomers exhibited a pKi in thisassay of 7.7 and 7.9 respectively; and Examples 21, 23 and 24 were nottested in this assay.

SYNTHETIC EXAMPLES

The invention will now be described by reference to the followingexamples which are merely illustrative and are not to be construed as alimitation of the scope of the present invention. All temperatures aregiven in degrees centigrade, all solvents are highest available purityand reactions were run under anhydrous conditions in an Argon (Ar)atmosphere where necessary.

¹H-NMR (hereinafter “NMR”) spectra were recorded at 400 MHz using aBruker AM 400 spectrometer or a Bruker AVANCE 400. Multiplicitiesindicated are: s=singlet, d=doublet, t=triplet, q=quartet, m=multipletand br indicates a broad signal. Flash chromatography was run over MerckSilica gel 60 (230-400 mesh) or equivalent in solvent mixtures asdescribed in each experiment.

satd=saturated; aq=aqueous; NMP=1-methyl-2-pyrrolidinone;DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone; SPE=solid phaseextraction; other abbreviations are as described in the ACS Style Guide(American Chemical Society, Washington, D.C., 1986).

General Procedures:

A) LC/MS (Liquid Chromatography/Mass Spectroscopy)

Waters ZQ mass spectrometer operating in positive ion electrospray mode,mass range 100-1000 amu.

UV wavelength: 215-330 nM

Column: 3.3 cm×4.6 mm ID, 3 μm ABZ+PLUS

Flow Rate: 3 ml/min

Injection Volume: 5 μl

Solvent A: 95% acetonitrile+0.05% formic acid

Solvent B: 0.1% formic acid+10 mM ammonium acetate

Gradient: 0% A/0.7 min, 0-100% A/3.5 min, 100% A/1.1 min, 100-0% A/0.2min

B) Mass Directed Automated Preparative HPLC Column, Conditions andEluent

The preparative column used was a Supelcosil ABZplus (10 cm×2.12 cminternal diameter; particle size 5 μm)

UV detection wavelength: 200-320 nM

Flow rate: 20 ml/min

Injection Volume: 0.5 ml

Solvent A: 0.1% formic acid

Solvent B: 95% acetonitrile+0.05% formic acid

Using the synthesis as shown in Scheme 1 the following intermediate andfinal compounds of Formula (I) as herein described have been made:

Compounds of Formula (I) and (Ia):

Example 17-Bromo-1,5-bis(2-chlorophenyl)-3,4-dihydro[1,6]naphthyridin-2(1H)-one

1a) 4,6-Dibromo-3-(bromomethyl)-2-(2-chlorophenyl)pyridine

Preparation of the title compound was synthesized as described in WO02/058695 whose disclosure is incorporated herein by reference in itsentirety.

1b) Tert-butyl 3-[4,6-Dibromo-2-(2-chlorophenyl)-3-pyridyl]propionate

n-Butyllithium in hexanes (1.6 Molar (hereinafter “M”), 3.75 millilitre(hereinafter “ml”), 6.0 millimole (hereinafter “mmol”)) was added todi-isopropylamine (0.84 ml, 6.0 mmol) in dry THF (15 ml) at −10° undernitrogen. After 5 minutes (hereinafter “min”). the solution was cooledto −70° and tert-butyl acetate (0.5 ml, 3.71 mmol) added dropwise. Afterstirring at −70° C. for 10 min. under nitrogen,4,6-Dibromo-3-(bromomethyl)-2-(2-chlorophenyl)pyridine (0.405 grams(hereinafter “g”), 0.92 mmol) in dry THF (15 ml) was added, and themixture stirred at −70° for 2 h. Glacial acetic acid (2 ml) was added,the temperature allowed to rise to 22° and the solution evaporated invacua. The residue was purified by column chromatography over silica (50g) eluting with cyclohexane-ethyl acetate (9:1)-(5:1) to give theproduct as an oil (0.21 g).

NMR: (400 MHz, CDCl₃) δ 7.75 (1H,s), 7.48-7.25(4H,3×m), 2.94, 2.75(2H,2×m), 2.38, 2.22(2H, 2×m), 1.36 (9H,s).

LC/MS R_(t) 3.91 min m/z 474/6/8 (MH+]

1c) 3-[4,6-Dibromo-2-(2-chlorophenyl)-3-pyridyl]propionic acid

Tert-butyl 3-[4,6-Dibromo-2-(2-chlorophenyl)-3-pyridyl]propionate (3.86g, 8.116 mmol) was dissolved in trifluoroacetic acid-water (9:1, 25 ml)and the solution allowed to stand for 3 about hours (hereinafter “h),then evaporated in vacuo. The residue was purified by columnchromatography over silica (70 g) eluting with cyclohexane-ethyl acetate(5:1)-(3:1) to give the product as an gum (1.39 g).

NMR (400 MHz, CDCl₃) δ 9.85 (1H,br s), 7.78 (1H,s), 7.46 (1H,dd), 7.38(1H,dt (1H,dt), 7.27 (1H,dd), 2.97, 2.80 (2H,2×m), 2.52, 2.39 (2H,2×m).

1d)N-(2-Chlorophenyl)-3-[4,6-dibromo-2-(2-chlorophenyl)-3-pyridinyl]propanamide

3-[4,6-Dibromo-2-(2-chlorophenyl)-3-pyridyl]propionic acid (1.09 g,2.603 mmol) was dissolved in toluene (25 ml)-methanol (5 ml), and a 2Msolution of trimethylsilyl-diazomethane in hexanes added (5 ml), and thesolution allowed to stand for about 0.5 hours. The solution wasevaporated in vacuo, and the resulting oil re-dissolved indichloromethane (25 ml). This solution was added slowly at 22° to atrimethylaluminium-2-chloroaniline complex [prepared by adding 2Mtrimethylaluminium in toluene (2.6 ml) to a solution of 2-chloroaniline(0.55 ml, 5.188 mmol) in dichloromethane (30 ml)] and the solutionstirred at 22° for 20 h under nitrogen. Water (15 ml) was added (veryslowly at first), followed by sufficient 2M hydrochloric acid todissolve all the precipitated aluminium salts. The organic phase wasseparated and the aqueous phase further extracted with dichloromethane(60 ml). The combined organic extracts were dried (Na₂SO₄), evaporatedin vacuo, and the oily residue purified by column chromatography oversilica (50 g) eluting with cyclohexane-ethyl acetate (100:0-70:30) toafford the title compound as a gum (0.95 g, 69%).

NMR (400 MHz, CDCl₃) δ 8.30 (1H,br d) 7.79 (1H,s), 7.52-7.20 (7H,m),7.02 (1H,br, t), 3.13-2.93 (2H,2×m), and 2.65-2.43 (2H,2×m).

LC/MS R_(t) 3.81 min m/z527/529/531/533 [MH⁺]

1 e)7-Bromo-1,5-bis(2-chlorophenyl)-3,4-dihydro[1,6]naphthyridin-2(1H)-one

N-(2-Chlorophenyl)-3-[4,6-dibromo-2-(2-chlorophenyl)-3-pyridinyl]propanamide(942 mg, 1.78 mmol) was divided into six portions and each dissolved inDMF (3 ml), and treated with potassium carbonate (50 mg, 0.362 mmol) andcopper(I) iodide (15 mg, 0.079 mmol), and heated in a Smith Creatormicrowave at 180° for 15 min. All reactions were then combined andevaporated in vacuo. The residue was treated with water (15 ml) andextracted with dichloromethane (2×20 ml). The extracts were passedthrough a hydrophobic frit and evaporated in vacuo. The residue waspurified by column chromatography over silica (20 g) eluting with acyclohexane-ethyl acetate gradient (100:0-0:100). (70:30) gave theproduct as a white foam (406 mg, 51%).

NMR (400 MHz, CDCl3) δ 7.67-7.63 (1H,m), 7.53-7.30 (7H,m), 6.32 (1H,s),3.05-2.68 (4H,2×m).

LC/MS R_(t) 3.55 min m/z44714491451 [MH⁺]

Example 2 7-Bromo-1,5-bis(2-chlorophenyl)[1,6]naphthyridin-2(1H)-one

7-Bromo-1,5-bis(2-chlorophenyl)-3,4-dihydro[1,6]naphthyridin-2(1H)-one(30 mg, 0.067 mmol) in carbon tetrachloride (5 ml) was treated with NBS(15 mg) and AIBN (1.1 mg) and heated under reflux for 1.5 h. DBU (10 μl)was added, the mixture cooled, and dichloromethane (5 ml) added,followed by 8% sodium bicarbonate (10 ml). The mixture was passedthrough a hydrophobic frit and evaporated in vacuo to give the productas an off-white solid.

NMR (400 MHz, CDCl3) δ 7.75-7.69 (1H,m), 7.60-7.33 (8H,m), 6.75 (1H,d),6.65 (1H,s)

LC/MS R_(t) 3.50 min m/z445/447/449 [MH⁺]

Example 31,5-Bis(2-Chlorophenyl)-7-[(2-hydroxy-1-(hydroxymethyl)ethyl]-amino][1,6]naphthyridin-2(1H)-one

7-Bromo-1,5-bis(2-chlorophenyl)f[1,6]naphthyridin-2(1H)-one (38 mg,0.085 mmol) was dissolved in NMP (2 ml) and serinol(2-amino-1,3-propanediol) (35 mg, 0.384 mmol) added, and the solutionheated in a Smith creator microwave at 220° for 0.5 h. After cooling,the solution was added to water (12 ml) and extracted withdichloromethane (10 ml). The mixture was passed through a hydrophobicfrit and evaporated in vacuo. The residue was purified by SPE (SiO₂, 10g) eluting with dichloromethane-methanol (98:2) to afford the titlecompound as a gum (9 mg, 23%).

NMR (400 MHz, CDCl3) δ 7.69-7.65 (1H,m), 7.55-7.30 (8H,m), 6.37 (1H,d),5.43 (1H,s), 5.30 (1H,br d), 3.90 (1H,m), 3.80-3.68 (4H,m), 1.63 (2H,brs).

LC/MS R_(t) 2.84 min m/z4561458 [MH⁺]

Example 4N-[2-[[1,5-bis(2-Chlorophenyl)-2-oxo-1,2-dihydro[1,6]naphthyridin-7-yl]amino]ethyl]acetamide

7-Bromo-1,5-bis(2-chlorophenyl)[1,6]naphthyridin-2(1H)-one (38 mg, 0.085mmol) was dissolved in NMP (2 ml) and N-acetylethylenediamine (300 mg,2.938 mmol) added, and the solution heated in a Smith creator microwaveat 220° for about 0.5 h. The NMP was removed using a vacuum centrifugeand the residue partitioned between 8% sodium bicarbonate (6 ml) anddichloromethane (10 ml). The mixture was passed through a hydrophobicfrit and evaporated in vacuo. The residue was purified by columnchromatography over silica (10 g) eluting with ethyl acetate and ethylacetate-methanol (9:1) to afford crude product. This was furtherpurified by chromatography over SCX-2 silica (0.5 g). Methanol elutedimpurities, and 2M ammonia in methanol gave the product as a white solid(12.7 mg, 32%).

NMR (400 MHz, CDCl3) δ 7.68 (1H,m), 7.58-7.37 (7H,m), 7.33 (1H,m), 6.65(1H,br s), 6.38 (1H,d), 5.35 (1H,s), 5.14 (1H,brt), 3.47-3.28 (4H,m),1.73 (3H,s).

LC/MS R_(t) 2.96 min m/z 467/469 [MH⁺]

Example 51,5-Bis(2-Chlorophenyl)-7-[(1H-imidazol-2-ylmethyl)amino[1,6]naphthyridin-2(1H)-one,formate salt

7-Bromo-1,5-bis(2-chlorophenyl)[1,6]naphthyridin-2(1H)-one (150 mg,0.336 mmol) was dissolved in NMP (5 ml), and 2-aminomethylimidazoledihydrochloride (286 mg, 1.682 mmol) and potassium carbonate (280 mg,2.026 mmol) added and the mixture heated in a Smith creator microwave at220° for about 0.5 h. The mixture was added to water and extracted withdichloromethane (1×10 ml, 1×5 ml), and the dichloromethane extractspassed down a hydrophobic frit, and evaporated in vacuo. The cruderesidue was passed down an SCX-2 cartridge (5 g), eluting with methanol,followed by 2M ammonia in methanol to elute the crude product. This waspurified by mass directed autoprep to afford the product as a gum (5.5mg, 3.5%).

NMR (400 MHz, MeOH-d⁴) δ 8.32 (>1H, s), 7.75-7.68 (1H,m), 7.64-7.35(7H,m), 7.31 (1H,ddd), 7.12 (2H,s), 6.33 (1H,d), 5.63 (1H,s), 4.60(2H,s).

LC/MS R_(t) 2.41 min m/z 462/464 [MH⁺]

Example 61,5-Bis(2-Chlorophenyl)-7-[[2-(Isopropylamino)ethyl]amino[1,6]naphthyridin-2(1H)-one,formate salt

7-Bromo-1,5-bis(2-chlorophenyl)[1,6]naphthyridin-2(1H)-one (59 mg, 0.132mmol) was dissolved in NMP (2 ml), and N-isopropylethylenediamine (0.2ml, 1.603 mmol) added and the mixture heated in a Smith creatormicrowave at 220° for 0.5 h. The crude reaction mixture was passed downan SCX-2 cartridge (20 g) eluting initially with methanol, followed by2M ammonia in methanol to elute the crude product. This was purified bymass directed autoprep (per general procedure B) to afford the productas a gum (12.6 mg, 19%).

NMR (400 MHz, MeOH-d⁴) δ 8.33 (1H,s), 7.78-7.72 (1H,m), 7.67-7.40(8H,m), 6.36 (1H,dd), 5.68 (1H,br s), 3.72-3.50 (2H,m), 3.26 (1H,m),3.20-3.10 (2H,m), 1.10 (6H,2×d).

LC/MS R_(t) 2.53 min m/z467/469 [MH⁺]

Example 7 1,5-Bis(2-Chlorophenyl)-7-yl-amino-1,6]naphthyridin-2(1H)-one

7-Bromo-1,5-bis(2-chlorophenyl)[1,6]naphthyridin-2(1H)-one reacted with2M amonia in MeOH to afford the title compound.

LC/MS R_(t) 3.00 min m/z 382/384 [MH⁺]

Example 8 1,5-Bis(2-Chlorophenyl)-7-chloro-[1,6]naphthyridin-2(1H)-one

7-Bromo-1,5-bis(2-chlorophenyl)[1,6]naphthyridin-2(1H)-one dissolved inNMP reacted with chloride ion in a Smith creator microwave at 220° forabout 30 minutes. Isolation by the method of example 5 afforded thetitle compound.

LC/MS R_(t) 3.49 min m/z 401/403/405 [MH⁺]

Using the synthesis as shown in Scheme 2, the following intermediate andfinal compounds of Formula (I, X═H) as herein described have been made:

Example 9 1-Benzyl-5-phenyl-1H-[1,6]naphthyridin-2-one

5-Phenyl-1H-[1,6]naphthyridin-2-one was prepared in accordance with thedisclosure of Lesher et. al., in U.S. Pat. No. 4,560,691 whosedisclosure is incorporated by reference herein (0.111 g, 0.5 mmol), andwas dissolved in DMF (2 mL) and stirred under argon. Potassium carbonate(0.066 g, 0.5 mmol) was added, and the mixture heated in an oil bath to100° C. for 1 hour. Benzyl bromide (0.086 g, 0.5 mmol) was added, andthe heating was continued for 6 hours. The solvent was removed in vacuo,and the residue was purified by preparative hplc. After evaporation ofthe fractions containing the desired product, the residue waspartitioned between ethyl acetate and 5% K₂CO₃, the organic phase waswashed with water, brine, dried over anhydrous Na₂SO₄, filtered, andevaporated to give the product which was then recrystallized frommethylene chloride/hexane to give the title compound as a whitecrystalline solid. mp 101-102° C.

Example 10

1,5-Diphenyl-1H-[1.6]naphthyridin-2-one

5-Phenyl-1H-[1,6]naphthyridin-2-one was prepared in accordance with thedisclosure of Lesher et. al., in U.S. Pat. No. 4,560,691 whosedisclosure is incorporated by reference herein (0.111 g, 0.5 mmol) andwas dissolved in CH₂Cl₂ (5 mL) and stirred under argon. Phenyl boronicacid (0.376 g, 3.0 mmol), triethylamine (0.42 mL, 3 mmol), and cupricacetate (0.362 g, 2 mmol0 was added, and the mixture stirred under argonat room temperature for 3 weeks. The solvent was removed in vacuo, andthe residue was partitioned between ethyl acetate and water, the organicphase was washed with water, brine, dried over anhydrous Na₂SO₄,filtered, and evaporated to give the product which was then flashchromatographed with ethyl acetate/hexane to give the title compound asa tan amorphous solid. mp 196-197° C.

Example 11 1-Methyl-5-phenyl-1H-[1,6]naphthyridin-2-one

The title compound was prepared in accordance with the disclosure ofLesher et. al., in U.S. Pat. No. 4,560,691 whose disclosure isincorporated by reference herein.

Example 12 5-Phenyl-1H-[1,6]naphthyridin-2-one

The title compound was prepared in accordance with the disclosure ofLesher et. al., in U.S. Pat. No. 4,560,691 whose disclosure isincorporated by reference herein. Using the synthesis as shown in Scheme4, the following intermediate and final compounds of Formula (I, X═H) asherein described have been made:

Example 13 1,5-bis(4-fluorophenyl)[1,8]naphthyridin-2(1H)-one

13a) N-(4-chloro-2-pyridinyl)-2,2-dimethylpropanamide

Triethylamine (6.8 mL, 48.6 mmol) was added to a stirred solution of4-chloro-2-aminopyridine, 11, (Townsend, L. B. et al Synthetic Commun.1997 27, 861-870) (5 g, 38.9 mmol) in dichloromethane (75 mL). Aftercooling to 0° C. a solution of trimethylacetyl chloride (5.3 mL, 42.8mmol) in dichloromethane (10 mL) was added dropwise over 15 min. Themixture was allowed to warm to 23° and stirred for 18 h then washed withsaturated sodium bicarbonate. The organic layer was dried (Na₂SO₄) andevaporated in vacuo to give an off-white solid. This was recrystallisedfrom isopropyl ether to afford the title compound as white crystals (5.5g, 67%). MS(EI) m/e 213, 215 [M+H]⁺.

13b) N-(4-chloro-3-formyl-2-pyridinyl)-2,2-dimethylpropanamide

A stirred solution of the compound of Example 13(a) (4 g, 18.8 mmol) inanhydrous tetrahydrofuran (40 mL) under a nitrogen atmosphere was cooledto −78° C. A 1.6M solution of n-butyllithium in hexanes (29.4 mL, 47.0mmol) was added dropwise over 20 min. After stirring for a further 30min a solution of anhydrous dimethylformamide (4.4 mL, 56.4 mmol) inanhydrous tetrahydrofuran (10 mL) was added dropwise over 10 min. Afterstirring at −78° C. for 1 h the mixture was allowed to warm to 23°. 6Mhydrochloric acid (100 mL) was added and stirring continued for 15 min.The organic layer was discarded and the aqueous layer adjusted to pH9-10by the addition of saturated potassium carbonate. This was extractedwith ethyl acetate and the organic extracts were dried (Na₂SO₄) andevaporated in vacuo to give a yellow semi-solid. Flash chromatography(silica gel, 1:1 ethyl acetate/petroleum ether) afforded the titlecompound as a white crystalline solid (4.1 g, 90%). MS(EI) m/e 241, 243[M+H]⁺.

13c) tert-butyl3-{4-chloro-2-[(2,2-dimethylpropanoyl)amino]-3-pyridinyl}-3-hydroxypropanoate

A 1.6M solution of n-butyllithium in hexanes (19.7 mL, 31.5 mmol) wasadded dropwise to a stirred solution of diisopropylamine (4.4 mL, 31.5mmol) in anhydrous tetrahydrofuran (30 mL) at −78° C. under a nitrogenatmosphere. After warming to 23° the solution was recooled to −78° C.and a solution of tert-butyl acetate (4.25 mL, 31.5 mmol) in anhydroustetrahydrofuran (10 mL) was added dropwise. After 15 min a solution ofthe compound of Example 13 (b) (3.61 g, 16 mmol) in anhydroustetrahydrofuran (15 mL) was added dropwise. The mixture was stirred at−78° C. for 30 min then allowed to warm to 23° and poured into water.This was extracted with ether and the organic extracts were washed withwater, dried (Na₂SO₄) and evaporated in vacuo. The residue wastriturated with ether and filtered to afford the title compound as awhite solid (3.78 g, 71%).

Flash chromatography of the mother liquor (silica gel, 3:2 ethylacetate/petroleum ether) afforded a second crop (0.6 g, 11%). MS(EI) m/e357, 359 [M+H]⁺.

13d) 5-chloro[1,8]naphthyridin-2(1H)-one

A stirred solution of the compound of Example 13 (c) (3.5 g, 9.8 mmol)in 3M hydrochloric acid (40 mL) was refluxed for 2.5 h. After cooling to23° the mixture was adjusted to pH 8 by the addition of saturatedpotassium carbonate. This was filtered and the solid washed with waterfollowed by ether then dried in vacuo at 60° C. to afford the titlecompound as a cream-coloured solid (1.04 g, 59%). MS(EI) m/e 181, 183[M+H]⁺.

13e) 5-(4-fluorophenyl)[1,8]naphthyridin-2(1H)-one

A stirred mixture of the compound of Example 13(d) (0.25 g, 1.38 mmol),4-fluorophenylboronic acid (0.23 g, 1.66 mmol),tetrakis(triphenylphosphine)palladium(0) (0.08 g, 0.07 mmol) and 2Mpotassium carbonate (1.87 mL, 3.74 mmol) in ethylene glycol dimethylether (5 mL) was refluxed for 24 h. The mixture was diluted withchloroform (200 mL), methanol (75 mL) and 5% sodium carbonate (75 mL)then heated until all solid material had dissolved. The layers wereseparated and the organic layer was dried (Na₂SO₄) and evaporated invacuo. The residue was triturated with methanol and filtered to affordthe title compound as a grey solid (0.27 g, 80%). MS(EI) m/e 241 [M+H]⁺.

13f) 1,5-bis(4-fluorophenyl)(1,8]naphthyridin-2(1H)-one

A mixture of the compound of Example 13 (e) (0.1 g, 0.42 mmol),4-fluorophenylboronic acid (0.12 g, 0.83 mmol), triethylamine (0.12 mL,0.83 mmol), pyridine (0.07 mL, 0.83 mL), copper (II) acetate (0.15 g,0.83 mmol) and powdered 4 Å sieves in dichloromethane (5 mL) was stirredat RT for 7 h. Further quantities of fluorophenylboronic acid (0.06 g),copper (II) acetate (0.075 g) and powdered 4 Å sieves were added andstirring continued for 18 h. The mixture was retreated as above andstirred for a further 5 h then diluted with dichloromethane (20 mL) andfiltered through a pad of celite. The filtrate was washed with saturatedsodium carbonate and water, dried (Na₂SO₄) and evaporated in vacuo togive a brown solid. Flash chromatography (silica gel, 2:1 petroleumether/ethyl acetate) afforded the title compound as a cream-colouredsolid (0.05 g, 36%). MS(EI) m/e 335 [M+H]⁺. ¹H NMR(400 MHz, d₆-DMSO) δ8.46 (d, J=5 Hz, 1H), 7.85 (d, J=10 Hz, 1H), 7.56-7.64 (m, 2H),7.31-7.49 (m, 6H), 7.27 (d, J=5 Hz, 1H), 6.77 (d, J=10 Hz, 1H).

Example 14

Preparation of5-(2,4-difluorophenyl)-1-(4-fluorophenyl)[1,8]naphthyridin-2(1H)-one14a) 5-(2,4-difluorophenyl)[1,8]naphthyridin-2(1H)-one

Following the procedure of Example 13(e), except substituting2,4-difluorophenylboronic acid for 4-fluorophenylboronic acid, the titlecompound was prepared (0.1 g, 26%). MS(EI) m/e 259 [M+H]⁺.

14b)5-(2,4-difluorophenyl)-1-(4-fluorophenyl)[1,8]naphthyridin-2(1H)-one

Following the procedure of Example 13(f), except substituting thecompound of Example 14(a) for the compound of Example 13(e), the titlecompound was prepared (0.04 g, 32%). MS(EI) m/e 353 [M+H]⁺. ¹H NMR (400MHz, d₆-DMSO) a 8.50 (d, 1H), 7.50-7.69 (m, 3H), 7.28-7.44 (m, 6H), 6.78(d, 1H).

Using the synthesis as shown in Scheme 6, the following intermediate andfinal compounds of Formula (I) as herein described have been made:

Example 151,5-Diphenyl-1H-7-[(2-hydroxy-1-(hydroxymethyl)ethyl]-amino]-[1,6]naphthyridin-2-one

15a) N-(2-chlorophenyl)-3-(2,6-dibromo-4-methoxyphenyl)propanamide

3-(2,6-dibromo-4-methoxyphenyl)propanoic acid (as described in WO02/058695, whose disclosure is incorporated by reference herein) (6.65g, 19.67 mmol) was dissolved in chloroform (150 ml) and thionyl chloride(15 ml) added, and the solution heated under reflux for 2 h. The solventwas removed in vacuo and the residue co-evaporated with chloroform (30ml). The acid chloride so formed was dissolved in chloroform (40 ml) andadded dropwise to a solution of 2-chloroaniline (5 ml, 47.53 mmol) anddi-isopropyl-ethylamine (10 ml, 57.43 mmol) in chloroform (150 ml) andthe solution was allowed to stand at 22° for 17 h. The homogeneoussolution washed with 2M hydrochloric acid (100 ml), passed through ahydrophobic frit and the organic phase evaporated in vacuo to give thetitle compound as a dark solid (7.53 g, 86%)

LC/MS R_(t) 3.81 min m/z446/448/450 [MH⁺]

15b) 5-Bromo-1-(2-chlorophenyl)-7-methoxy-3,4-dihydro-2(1H)-quinolinone

N-(2-chlorophenyl)-3-(2,6-dibromo-4-methoxyphenyl)propanamide (1.40 g,3.128 mmol), copper(I) iodide (0.895 g, 4.694 mmol), and potassiumcarbonate (0.865 g, 6.259 mmol) in DMF (15 ml), were heated under refluxfor 30 min., cooled and evaporated in vacuo. The residue was treatedwith 2M hydrochloric acid (80 ml) and extracted with dichloromethane(2×50 ml). The extracts were passed through a hydrophobic frit,evaporated in vacuo and the residue purified by flash chromatographyover silica (50 g) eluting with cyclohexane-ethyl acetate gradient(100:0-50:50) to give the product as a white solid (0.714 g, 62%)

LC/MS R_(t) 3.46 min m/z 366/368/370 [MH⁺]

15c) 1,5-bis(2-chlorophenyl)-7-methoxy-3,4-dihydro-2(1H)-quinolinone

5-Bromo-1-(2-chlorophenyl)-7-methoxy-3,4-dihydro-2(1H)-quinolinone (2.10g, 5.728 mmol), and 2-chlorophenylboronic acid (1.77 g, 11.32 mmol) weredissolved in toluene (40 ml)-ethanol (15 ml), and 1M aqueous sodiumcarbonate (15 ml) added. Nitrogen gas was passed through the mixture for2 min., then tetrakis(triphenylphosphine)-palladium(0) (0.3 g) added,and the mixture stirred under reflux under nitrogen for 3.5 h. Theorganic phase was separated, dried (Na₂SO₄), and evaporated in vacuo andthe residue purified by flash chromatography over silica (70 g) elutingwith cyclohexane-ethyl acetate gradient to afford the title compound asa white solid (1.98 g, 87%)

LC/MS R_(t) 3.67 min m/z 398/400 [MH⁺]

15d) 1,5-bis(2-chlorophenyl)-7-methoxy-2(1H)-quinolinone

1,5-bis(2-chlorophenyl)-7-methoxy-3,4-dihydro-2(1H)-quinolinone (0.85 g,2.134 mmol) and manganese dioxide (5 g) were heated in chlorobenzene (50ml) under reflux for 17 h. After cooling, the chlorobenzene was removedin vacuo, ethyl acetate (80 ml) added to the residue, then filteredthrough celite. The filtrate was evaporated in vacuo to afford the titlecompound as a yellow solid (0.82 g, 97%)

LC/MS R_(t) 3.54 min m/z 396/398/400 [MH⁺]

15e) 1,5-bis(2-chlorophenyl)-7-hydroxy-2(1H)-quinolinone

1,5-bis(2-chlorophenyl)-7-methoxy-2(1H)-quinolinone (0.863 g, 2.178mmol) was dissolved in dichloromethane (40 ml) and 1M boron tribromidein dichloromethane (12 ml) added slowly under nitrogen. The solution wasstirred at 21° for 4 h, then quenched carefully with methanol (3 ml) andice (25 g). The mixture was passed through a hydrophobic frit, and theaqueous phase further extracted with dichloromethane (20 ml), and passedthrough a hydrophobic frit. The dichloromethane extracts were combinedand evaporated in vacuo to afford the title compound as a dark solid(0.7849, 94%).

LC/MS R_(t) 3.40 min m/z 382/4 [MH⁺]

15f) 1,5-bis(2-chlorophenyl)-2-oxo-1,2-dihydro-7-quinolinyltrifluoromethanesulfonate

1,5-bis(2-chlorophenyl)-7-hydroxy-2(1H)-quinolinone (0.216 g, 0.565mmol) and triethylamine (4 ml) were dissolved in dichloromethane (30 ml)and N-phenyltrifluoromethylsulfonimide (0.403 g, 1.128 mmol) added andthe resulting solution stirred at 22° for 1 h, and evaporated in vacuo.The residue was purified by flash chromatography over silica (50 g)eluting with cyclohexane-ethyl acetate gradient (100:0-50:50) to affordthe title compound as a white solid (0.14 g, 48%).

LC/MS R_(t) 2.84 min m/z 456/458 [MH⁺]

15 g)1,5-bis(2-chlorophenyl)-7-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-2(1H)-quinolinone

1,5-bis(2-chlorophenyl)-2-oxo-1,2-dihydro-7-quinolinyltrifluoromethanesulfonate (50 mg, 0.097 mmol), serinol (44 mg, 0.483mmol), racemic BINAP (74 mg, 0.19 mmol), palladium(II) acetate (17 mg,0.076 mmol), and cesium carbonate (0.14 g, 0.43 mmol) in 1,4-dioxan (2ml) were heated in a Smith creator microwave at 1300 for 15 min. Water(3 ml) and chloroform (4 ml) were added to the reaction mixture, whichwas then passed through a hydrophobic frit, and blown down under astream of nitrogen. The residue was purified by mass directed autoprepto afford the title compound as a gum (7 mg, 16%).

LC/MS R_(t) 2.88 min m/z4551457 [MH⁺]

Example 161,5-Bis(2-chlorophenyl)-7-{[2-(isopropylamino)ethyl]amino}-2(1H)-quinolinone

1,5-bis(2-chlorophenyl)-2-oxo-1,2-dihydro-7-quinolinyltrifluoromethanesulfonate (50 mg, 0.097 mmol),N-isopropylethylenediamine (0.36 ml, 2.885 mmol), racemic BINAP (74 mg,0.119 mmol), palladium(II) acetate (17 mg, 0.076 mmol), and cesiumcarbonate (0.14 g, 0.43 mmol) in 1,4-dioxan (4 ml) were heated underreflux under nitrogen for 2 h. The solvent was removed in vacuo, and theresidue partitioned between water (8 ml) and dichloromethane (10 ml).The mixture was passed through a hydrophobic trit, and the filtratepassed though two 5 g SCX-2 cartridges, and eluted with methanolfollowed by 2M ammonia in methanol. The latter fractions were evaporatedin vacuo and the residue purified by mass directed autoprep (per generalprocedure B) to afford the title compound as a gum (5.3 mg, 10%).

LC/MS R_(t) 2.54 min m/z4661468 [MH⁺]

Example 17

6-bromo-1,5-bis(2-chlorophenyl)-7-(methyloxy)-2(1H)-quinolinone

The product of example 15(c) was reacted by the procedure of example 2.The cooled reaction mixture was diluted with ethyl acetate (20 ml), andwashed with 2M hydrochloric acid (10 ml), dried (Na₂SO₄) and evaporatedin vacuo. The residue was purified by flash chromatography over silica(20 g) eluting with cyclohexane-ethyl acetate (100:0-0:100 gradient) toafford the two isomers of the title compound as white solids.

Isomer 1:

TLC R_(f)=0.29 (SiO₂ cyclohexane-ethyl acetate 1:1)

LC/MS R_(t) 3.64 min m/z 474/476/478 [MH⁺]

Isomer 2:

TLC R_(t)=0.21 (SiO₂ cyclohexane-ethyl acetate 1:1)

LC/MS R_(t) 3.65 min m/z474/476/478 [MH⁺]

Using the synthesis as shown in Scheme 7, the following intermediate andfinal compounds of Formula (I, X═H) as herein described have been made:

Example 18

5-(2-fluorophenyl)-1-(4-flourophenyl)-2(1H)-quinolinone 18a)5-quinolinyl triflouromethanesulfonate

Pyridine (1.67 mL, 20.6 mmol) was added to a stirred suspension of5-hydroxyquinoline (1.0 g, 6.89 mmol) in CH₂Cl₂ at 0° C. under anatmosphere of nitrogen. A solution of triflouromethanesulfonic anhydride(1.74 mL, 10.3 mmol) in dichloromethane (30 mL) was added dropwise over40 min. The mixture was allowed to warm to RT and poured into 2M aqueoushydrochloric acid (50 mL) with vigorous stirring. The mixture was washedwith saturated sodium bicarbonate. The organic layer was dried (MgSO₄)and evaporated in vacuo to give a red oil. Flash chromatography (silicagel, 1:4 ethyl acetate/cyclohexane) afforded the title compound as ayellow oil (1.62 g, 85%). MS(EI) m/e 278 [M+H]⁺.

18b) 5-(2-flourophenyl)quinoline

A stirred mixture of the compound of Example 18(a) (0.95 g, 3.43 mmol),2-fluorophenylboronic acid (0.72 g, 5.14 mmol),tetrakis(triphenylphosphine)palladium(0) (0.1 g, 0.03 mmol) andpotassium carbonate (1.42 g, 10.28 mmol) in 1,4-dioxane (60 mL) andwater (20 mL) was refluxed for 1.5 h. The mixture was extracted withethyl acetate. The combined extracts were dried (MgSO₄) and evaporatedin vacuo to give a brown oil. Flash chromatography (silica gel, 1:4ethyl acetate/cyclohexane) afforded the title compound as a pale yellowcrystalline solid (0.58 g, 72%). MS(EI) m/e 224 [M+H]⁺.

18c) 5-(2-fluorophenyl)quinoline 1-oxide

3-chloroperoxybenzoic acid (0.661 g, 3.83 mmol) was added portion-wiseto a stirred solution of the compound of Example 18(b) (0.57 g, 2.55mmol) in chloroform (6 mL) at room temperature (hereinafter “RT”). Thereaction was stirred for 2 h then diluted with chloroform (100 mL),washed with saturated sodium metabisulfite, saturated sodiumbicarbonate, water and saturated sodium chloride, dried (MgSO₄) andevaporated in vacuo to afford the title compound as a cream-colouredsolid (0.475 g, 78%). MS(EI) m/e 240 [M+H]⁺.

18d) 5-(2-fluorophenyl)-2(1H)-quinolinone

Paratoluenesulfonyl chloride (0.4 g, 2.14 mmol) and 10% aqueouspotassium carbonate (20 mL) were added to a stirred solution of thecompound of Example 18(c) (0.465 g, 1.94 mmol) in chloroform (10 mL).The reaction was stirred vigorously for 3 h then diluted with chloroform(100 mL). The organic layer was washed with water and saturated sodiumchloride, dried (MgSO₄) and evaporated in vacuo. Flash chromatography(silica gel, 5% methanol/dichloromethane) afforded the title compound asa cream-coloured solid (0.349 g, 75%). MS(ES) m/e 240 [M+H]⁺.

18e) 5-(2-fluorophenyl)-1-(4-fluorophenyl)-2(1H)-quinolinone

A mixture of the compound of Example 18(d) (0.1 g, 4.18 mmol),4-fluorophenylboronic acid (0.118 g, 0.836 mmol), triethylamine (0.116mL, 0.836 mmol), pyridine (0.068 mL, 0.836 mmol), copper (II) acetate(0.156 g, 0.836 mmol) and powdered 4 Å sieves in dichloromethane (10 mL)was stirred at RT for 7 h. Further quantities of fluorophenylboronicacid (0.06 g), copper (II) acetate (0.075 g) and powdered 4 Å sieveswere added and stirring continued for 18 h. The mixture was retreated asabove and stirred for a further 5 h then diluted with dichloromethane(20 mL) and filtered through a pad of celite. The filtrate was washedwith saturated sodium carbonate and water, dried (Na₂SO₄) and evaporatedin vacuo to give a brown solid. Flash chromatography (silica gel, 1:1cyclohexane/ethyl acetate) afforded the title compound as a pale brownsolid (0.106 g, 76%). MS(EI) m/e 334 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.65 (d of d, J=10 and 5 Hz, 1H), 7.5-7.2 (m, 9H), 7.18 (d, J=8 Hz, 1H),6.73 (d, J=10 Hz, 1H), 6.71 (d, J=10 Hz, 1H).

Example 19 5-(4-fluorophenyl)-1-(4-fluorophenyl)-2(1H)-quinolinone

19a) 5-(4-fluorophenyl)quinoline

Following the procedure of Example 18(b), except substituting4-fluorophenylboronic acid for 2-fluorophenylboronic acid, the titlecompound was prepared (0.78 g, 97%). MS(EI) m/e 224 [M+H]⁺.

19b) 5-(4-fluorophenyl)quinoline 1-oxide

Following the procedure of Example 18(c), except substituting thecompound of Example 19(a) for the compound of Example 18(b), the titlecompound was prepared (0.475 g, 78%). MS(EI) m/e 240 [M+H]⁺.

19c) 5-(4-fluorophenyl)-2(1H)-quinolinone

Following the procedure of Example 18(d), except substituting thecompound of Example 19(b) for the compound of Example 18(c), the titlecompound was prepared (0.364 g, 47%). MS(EI) m/e 240 [M+H]⁺.

19d) 5-(4-fluorophenyl)-1-(4-fluorphenyl)-2(1H)-quinolinone

Following the procedure of Example 18(e), except substituting thecompound of Example 19(c) for the compound of Example 18(d), the titlecompound was prepared (0.061 g, 44%). MS(EI) m/e 334 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.82 (d of d, J=10 and 1 Hz, 1H), 7.4-6.88 (m, 10H), 6.72(d, J=10 Hz, 1H), 6.68 (d, J=10 Hz, 1H).

Example 20 5-(2,4-difluorophenyl)-1-(4-fluorophenyl)-2(1H)-quinolinone

20a) 5-(2,4-difluorophenyl)quinoline

Following the procedure of Example 18(b), except substituting2,4-difluorophenylboronic acid for 2-fluorophenylboronic acid, the titlecompound was prepared (0.71 g, 81%). MS(EI) m/e 242 [M+H]⁺.

20b) 5-(2,4-difluorophenyl)quinoline 1-oxide

Following the procedure of Example 18(c), except substituting thecompound of Exampe 20(a) for the compound of Example 18(b), the titlecompound was prepared (0.53 g, 83%). MS(EI) m/e 258 [M+H]⁺.

20c) 5-(2,4-difluorophenyl)-2(1H)-quinolinone

Following the procedure of Example 18(d), except substituting thecompound of Example 20(b) for the compound of Example 18(c), the titlecompound was prepared (0.304 g, 63%). MS(EI) m/e 258 [M+H]⁺.

20d) 5-(2,4-difluorophenyl)-1-(4-fluorphenyl)-2(1H)-quinolinone

Following the procedure of Example 18(e), except substituting thecompound of Example 20(c) for the compound of Example 18(d), the titlecompound was prepared (0.078 g, 53%). MS(EI) m/e 352 {M+H]⁺. ¹H NMR(400MHz, CDCl₃) δ 7.6 (d of d, J=10 and 1 Hz, 1H), 7.4 (t, J=8 Hz, 1H), 7.32(m, 6H), 7.14 (d, J=10 Hz, 1H), 2H), 6.74 (d, J=10 Hz, 1H), 6.71 (d,J=10 Hz, 1H).

Example 21 5-(4-methylphenyl)-1-(4-fluorophenyl)-2(1H)-quinolinone

Following the procedures of Examples 18 to 20 above, the title compoundwas prepared.

Using the synthesis as shown in Scheme 3, the following intermediate andfinal compounds of Formula (I) as herein described have been made:

Example 22 7-chloro-1,5-bis(2-chlorophenyl)[1,8]naphthyridin-2(1H)-one

22a) 3-(Bromomethyl)-2,6-dichloro-4-(2-chlorophenyl)pyridine

The title compound was prepared in a series of steps starting from thecommercially cyanoacetamide and methyl 3-(2-chlorophenyl)-2-propynoateby known literature procedures, such as those noted in InternationalPublication No. WO 02/058695 A1.

LC/MS R_(t) 3.75 min m/z 350/352/354 [MH+]

22b) tert-Butyl3-[2,6-dichloro-4-(2-chlorophenyl)-3-pyridinyl]propanoate

n-Butyllithium in hexanes (1.6M, 18 ml, 28.8 mmol) was added todi-isopropylamine (4.1 ml, 29.25 mmol) in dry THF (200 ml) at −10° undernitrogen. After 5 min. the solution was cooled to −70° and tert-butylacetate (3.9 ml, 28.93 mmol) added dropwise. After stirring at −70° for15 min. under nitrogen,3-(bromomethyl)-2,6-dichloro-4-(2-chlorophenyl)pyridine (2.44 g, 6.942mmol) in dry THF (18 ml) was added dropwise over 10 min., and themixture stirred at −70° for 1 h. Glacial acetic acid (2.3 ml) was added,the temperature allowed to rise to 22° and brine (200 ml) and ethylacetate (100 ml) added. The phases were separated and the aqueousfurther extracted with ethyl acetate (150 ml). The extracts were dried(Na2SO4), evaporated in vacuo and the residue purified by flashchromatography over silica eluting with cyclohexane-ethyl acetate(100:0-50:50) to give the title compound as a viscous gum (2.44 g, 91%).

LC/MS R_(t) 4.01 min m/z 386/388/390 [MH+]

22c) Methyl 3-[2,6-dichloro-4-(2-chlorophenyl)-3-pyridinyl]propanoate

tert-Butyl 3-[2,6-dichloro-4-(2-chlorophenyl)-3-pyridinyl]propanoate(2.44 g, 6.31 mmol) was dissolved in anisole (6 ml) and trifluoroaceticacid (30 ml) added and the solution allowed to stand at 21° for 2 h,then evaporated in vacuo. The residue was dissolved in toluene (40ml)-methanol (10 ml), and a 2M solution of trimethylsilyldiazomethane inhexanes added (8 ml), and the solution allowed to stand for 0.5 h. Thesolution was evaporated in vacuo, and the resulting oil purified byflash chromatography over silica eluting with cyclohexane-ethyl acetate(100:0-65:35) to give the title compound as a viscous gum (1.40 g, 64%)

LC/MS R_(t) 3.80 min m/z 344/346 [MH+]

22d)N-(2-chlorophenyl)-3-[2,6-dichloro-4-(2-chlorophenyl)-3-pyridinyl]propanamide

2-Chloroaniline (0.87 ml, 8.21 mmol) in dichloromethane (80 ml) wastreated with 2M trimethylaluminium in toluene (4.1 ml, 8.2 mmol) at 0-5°under nitrogen. After stirring for 15 min. a solution of methyl3-[2,6-dichloro-4-(2-chlorophenyl)-3-pyridinyl]propanoate (1.40 g, 4.063mmol) in dichloromethane (40 ml) was added and the solution stirred at21° for 17 h. Water (15 ml) was added (very slowly at first), followedby sufficient 2M hydrochloric acid to dissolve all the precipitatedaluminium salts. The organic phase was separated and the aqueous phasefurther extracted with dichloromethane (50 ml). The combined organicextracts passed through a hydrophobic frit, evaporated in vacuo, and theoily residue purified by column chromatography over silica (70 g)eluting with cyclohexane-ethyl acetate (100:0-65:35) to afford the titlecompound as a gum (1.52 g, 85%).

LC/MS R_(t) 3.84 min m/z 439/441/443 [MH+]

22e)7-chloro-1,5-bis(2-chlorophenyl)-3,4-dihydro[1,8]naphthyridin-2(1H)-one

3-[6-Chloro-4-(2-chlorophenyl)-3-pyridinyl]-N-(2-chlorophenyl)propanamide(1.51 g, 3.43 mmol) was dissolved in DMF (40 ml), potassium carbonate(0.95 g, 6.87 mmol) and copper(I) iodide (1.3 g, 6.83 mmol) added andthe mixture heated at reflux for 1 h. Most of the DMF was removed invacuo, the residue was treated with water (10 ml) and brine (10 ml), andextracted with dichloromethane (2×15 ml) and ethyl acetate (15 ml). Theextracts were passed through a hydrophobic frit and evaporated in vacuoto give the title compound as an off-white solid (1.6 g)

LC/MS R_(t) 4.01 min m/z 403/405/407 [MH+]

22f) 7-chloro-1,5-bis(2-chlorophenyl)[1,8]naphthyridin-2(1H)-one

7-Chloro-1,5-bis(2-chlorophenyl)-3,4-dihydro[1,8]naphthyridin-2(1H)-one(220 mg, 0.545 mmol) in carbon tetrachloride (3 ml) was treated with NBS(110 mg; 0.618 mmol) and AIBN (1 mg) and heated under reflux for 1 h.Further NBS (110 mg, 0.618 mmol) and AIBN (2 mg) were added and heatingunder reflux continued for a further 2 h. DBU (0.2 ml) was added, themixture cooled, filtered, and further carbon tetrachloride (3 ml) added,followed by 2M hydrochloric acid (3 ml). The mixture was purified bycolumn chromatography over silica (20 g) eluting with cyclohexane-ethylacetate (100:0-60:40) to afford the title compound as a white solid (151mg, 69%).

LC/MS R_(t) 3.75 min m/z 401/403/405 [MH+]

Example 23

1,5-bis(2-chlorophenyl)-7-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}[1,8]naphthyridin-2(1H)-oneformate

7-chloro-1,5-bis(2-chlorophenyl)[1,8]naphthyridin-2(1 h-one (73 mg,0.182 mmol) and serinol (75 mg, 0.823 mmol) were dissolved inN-methylpyrrolidinone (2 ml) and heated in a Smith Creator microwave at220° for 30 min. The mixture was evaporated in vacuo using a vacuumcentrifuge, and the residue purified by mass directed autoprep HPLC (pergeneral procedure B) to afford the title compound as a white solid (33mg, 36%) NMR (400 MHz, CDCl₃) δ 7.65-7.55 (2H,m), 7.52-7.42 (4H,m),7.40-7.29 (3H,m), 6.40 (1H,s), 6.35 (1H,dd), 3.55-3.42 (5H,m)

LC/MS R, 2.84 min m/z4561458 [MH⁺]

Example 24

1,5-bis(2-chlorophenyl)-7-{[2-(isopropylamino)ethyl]amino}[1,8]naphthyridin-2(1H)-oneformate

7-chloro-1,5-bis(2-chlorophenyl)[1,8]naphthyridin-2(1H)-one (73 mg,0.182 mmol) and N-isopropylethylenediamine (0.14 ml, 1.122 mmol) weredissolved in N-methylpyrrolidinone (2 ml) and heated in a Smith Creatormicrowave at 220° for 30 min. The solution was passed down an SCX-2cartridge (10 g) and eluted with methanol, followed by 2M ammonia inmethanol. The latter eluate was evaporated in vacuo and the residuepurified by mass directed autoprep HPLC (per General procedure B) toafford the title compound as a clear gum (24 mg, 26%)

NMR (400 MHz, CDCl₃) δ 7.58-7.48 (2H,m), 7.45-7.22 (7H,m), 6.43 (1H,d),6.28,6.25 (1H,2×s), 3.37-3.19 (2H,m), 3.12 (1H,m), 2.83-2.58 (2H,m),1.20 (6H,d)

LC/MS R_(t) 2.49 min m/z4671469 [MH⁺]

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The above description fully discloses the invention including preferredembodiments thereof. Modifications and improvements of the embodimentsspecifically disclosed herein are within the scope of the followingclaims. Without further elaboration, it is believed that one skilled inthe are can, using the preceding description, utilize the presentinvention to its fullest extent. Therefore, the Examples herein are tobe construed as merely illustrative and not a limitation of the scope ofthe present invention in any way. The embodiments of the invention inwhich an exclusive property or privilege is claimed are defined asfollows.

1. A compound of the formula:

wherein R₁ is an optionally substituted aryl or an optionallysubstituted heteroaryl ring; X is R₂, OR₂, S(O)_(m)R₂,(CH₂)_(n)N(R₁₀)S(O)_(m)R₂, (CH₂)_(n)N(R₁₀)C(O)R₂, (CH₂)_(n)NR₄R₁₄,NR₂(CH₂)_(n)NR₄R₁₄, O(CH₂)_(n)NR₄R₁₄, S(CH₂)_(n)NR₄R₁₄, (CH₂)_(n)J,NR₂(CH₂)_(n)J, O(CH₂)_(n)J, S(CH₂)_(n)J, or (CH₂)_(n)N(R₂)₂; J is anoptionally substituted heteroaryl ring; n is 0 or an integer having avalue of 1 to 10; m is 0 or an integer having a value of 1 or 2; q is 0or an integer having a value of 1 to 10; R₂ is hydrogen, C₁₋₁₀ alkyl,aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, which moietiesare all optionally substituted, or R₂ is the moietyX₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or C(A₁)(A₂)(A₃); X₁ is N(R₁₀), O,S(O)_(m), or CR₁₀R₂₀; X₂ is independently hydrogen, halogen or C₁₋₄alkyl; A₁ is an optionally substituted C₁₋₁₀ alkyl; A₂ is an optionallysubstituted C₁₋₁₀ alkyl; A₃ is hydrogen or is an optionally substitutedC₁₋₁₀ alkyl; G₁ is C—X₂; R₃ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkyl moiety, which moietiesare optionally substituted; provided that when G₁ is C—X₂, X₂ ishydrogen, R₁ is an optionally substituted phenyl, X is R₂ and R₂ ishydrogen then R₃ is not methyl; R₄ and R₁₄ are each independentlyselected from hydrogen, optionally substituted C₁₋₄ alkyl, optionallysubstituted aryl, or optionally substituted aryl-C₁₋₄ alkyl, arylC₁₋₁₀alkyl, heteroaryl or heteroarylC₁₋₁₀ alkyl, wherein each of thesemoieties may be optionally substituted; R₁₀ and R₂₀ are independentlyselected from hydrogen or C₁₋₄alkyl; or a pharmaceutically acceptablesalt thereof.
 2. The compound according to claim 1 which is Formula(II), or a pharmaceutically acceptable salt thereof.
 3. The compoundaccording to claim 1 which is Formula (IIa), or a pharmaceuticallyacceptable salt thereof.
 4. The compound according to claim 1 wherein R₁is an optionally substituted phenyl or naphthyl.
 5. The compoundaccording to claim 4 wherein the phenyl is substituted one or more timesindependently by halogen, alkyl, hydroxy, alkoxy, amino, orhalosubstituted alkyl.
 6. The compound according to claim 5 wherein thesubstituents are independently chlorine, fluorine, C₁₋₄ alkyl, or CF₃.7. The compound according to claim 5 wherein the phenyl ring issubstituted in the 2, 4, or 6-position, di-substituted in the2,4-position, or tri-substituted in the 2,4,6-position.
 8. The compoundaccording to claim 1 wherein X is OR₂, or S(O)_(m)R₂.
 9. The compoundaccording to claim 1 wherein X is (CH₂)_(n)NR₄R₁₄, or (CH₂)_(n)N(R₂)₂.10. The compound according to claim 1 wherein X is R₂ or(CH₂)_(n)N(R₁₀)S(O)_(m)R₂, or (CH₂)_(n)N(R₁₀)C(O)R₂.
 11. The compoundaccording to claim 1 wherein R₂, other than hydrogen, is optionallysubstituted independently one or more times with C₁₋₁₀ alkyl,halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl, C₅₋₇cycloalkenyl, C₅₋₇cycloalkenyl C₁₋₁₀ alkyl, halogen, —C(O), cyano, nitro,(CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH, (CR₁₀R₂₀)_(n)S(O)_(m)R₇,(CR₁₀R₂₀)_(n)NR₁₀S(O)₂R₇, (CR₁₀R₂₀)_(n)NR₄R₁₄, (CR₁₀R₂₀)_(n)CN,(CR₁₀R₂₀)_(n)S(O)₂NR₄R₁₄, (CR₁₀R₂₀)_(n)C(Z)R₆, (CR₁₀R₂₀)_(n)OC(Z)R₆,(CR₁₀R₂₀)_(n)C(Z)OR₆, (CR₁₀R₂₀)_(n)C(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)R₆,(CR₁₀R₂₀)_(n)NR₁C(═NR₁₀)NR₄R₁₄, (CR₁₀R₂₀)_(n)C(═NOR₆)NR₄R₁₄,(CR₁₀R₂₀)_(n)OC(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₄R₁₄, or(CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₇; and wherein R₆ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, heterocyclyl, heterocyclyl C₁₋₁₀alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl or heteroarylC₁₋₁₀ alkyl, wherein these moieties,excluding hydrogen, are optionally substituted; R₇ is C₁₋₆alkyl, aryl,arylC₁₋₆alkyl, heterocyclic, heterocyclylC₁₋₁₆ alkyl, heteroaryl, orheteroarylC₁₋₆alkyl; and wherein each of these moieties are optionallysubstituted.
 12. The compound according to claim 8 wherein R₂ is anoptionally substituted alkyl.
 13. The compound according to claim 12wherein the alkyl is an optionally substituted by (CR₁₀R₂₀)_(n)C(Z)OR₆,(CR₁₀R₂₀)_(n)OR₆, or (CR₁₀R₂₀)_(n)NR₄R₁₄ and R₆ is hydrogen, C₁₋₁₀alkyl, C₃₋₇ cycloalkyl, heterocyclyl, heterocyclyl C₁₋₁₀alkyl, aryl,arylC₁₋₁₀ alkyl, heteroaryl or heteroarylC₁₋₁₀ alkyl, and wherein the R₆moieties, excluding hydrogen, are optionally substituted.
 14. Thecompound according to claim 1 wherein R₂ is theX₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or C(A₁)(A₂)(A₃).
 15. The compoundaccording to claim 14 wherein X₁ is oxygen or N(R10).
 16. The compoundaccording to claim 14 wherein at least one of A₁, A₂ or A₃ issubstituted by (CR₁₀R₂₀)_(n)OR₆ and R₆ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, heterocyclyl, heterocyclyl C₁₋₁₀alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl or heteroarylC₁₋₁₀ alkyl, and wherein the R₆ moieties,excluding hydrogen, are optionally substituted.
 17. The compoundaccording to claim 16, wherein q is 1 or
 2. 18. The compound accordingto claim 1 wherein R₃ is an optionally substituted C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₄alkyl, aryl, arylC₁₋₁₀ alkyl.
 19. Thecompound according to claim 18 wherein R₃ is optionally substituted oneor more times independently with C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl, C₅₋₇cycloalkenyl, C₅₋₇cycloalkenylC₁₋₁₀ alkyl, halogen, cyano,nitro, (CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH, (CR₁₀R₂₀)_(n)S(O)_(m)R₇, (CR₁OR₂₀)_(n)NR₁₀S(O)₂R₇, (CR₁₀R₂₀)_(n)NR₄R₁₄, (CR₁₀R₂₀)_(n)CN,(CR₁₀R₂₀)_(n)S(O)₂NR₄R₁₄, (CR₁₀R₂₀)_(n)C(Z)R₆, (CR₁₀R₂₀)_(n)OC(Z)R₆,(CR₁₀R₂₀)_(n)C(Z)OR₆, (CR₁₀R₂₀)_(n)C(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)R₆,(CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₀)NR₄R₁₄, (CR₁₀R₂₀)_(n)OC(Z)NR₄R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₄R₁₄, or (CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₇; and wherein R₆is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, heterocyclylC₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl or heteroarylC₁₋₁₀ alkyl,wherein these moieties, excluding hydrogen, are optionally substituted;R₇ is C₁₋₆alkyl, aryl, arylC₁₋₆alkyl, heterocyclic, heterocyclylC₁₋₆alkyl, heteroaryl, or heteroarylC₁₋₆alkyl; and wherein each of thesemoieties are optionally substituted.
 20. The compound according to claim19 wherein the optional substituent is halogen, C₁₋₁₀ alkyl, hydroxy,alkoxy, amino, or halosubstituted C₁₋₁₀ alkyl.
 21. The compoundaccording to claim 1 wherein X₂ is hydrogen.
 22. The compound accordingto claim 1, which is:1,5-bis(4-fluorophenyl)[1,8]naphthyridin-2(1H)-one; and5-(2,4-difluorophenyl)-1-(4-fluorophenyl)[1,8]naphthyridin-2(1H)-one;and1,5-bis(2-chlorophenyl)-7-{[2-(isopropylamino)ethyl]amino}[1,8]naphthyridin-2(1H)-one;and1,5-bis(2-chlorophenyl)-7-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}[1,8]-naphthyridin-2(1H)-one;or a pharmaceutically acceptable salt thereof.
 23. A pharmaceuticalcomposition comprising an effective amount of a compound according toclaim 1 and a pharmaceutically acceptable carrier or diluent.
 24. Amethod of treating a CSBP/RK/p38 mediated disease in a mammal in needthereof comprising administering to said mammal an effective amount of acompound according to claim
 1. 25. The method according to claim 24wherein the CSBP/RK/p38 kinase mediated disease is psoriatic arthritis,Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acutesynovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis,gouty arthritis and other arthritic condition, sepsis, septic shock,endotoxic shock, gram negative sepsis, toxic shock syndrome, cerebralmalaria, meningitis, ischemic and hemorrhagic stroke, neurotrauma/closedhead injury, asthma, adult respiratory distress syndrome, chronicpulmonary inflammatory disease, chronic obstructive pulmonary disease,silicosis, pulmonary sarcososis, bone resorption disease, osteoporosis,restenosis, cardiac and brain and renal reperfusion injury, congestiveheart failure, coronary arterial bypass grafting (CABG) surgery,thrombosis, glomerularnephritis, chronic renal failure, diabetes,diabetic retinopathy, macular degeneration, graft vs. host reaction,allograft rejection, inflammatory bowel disease, Crohn's disease,ulcerative colitis, neurodegenarative disease, muscle degeneration,diabetic retinopathy, macular degeneration, tumor growth and metastasis,angiogenic disease, influenza induced pneumonia, eczema, contactdermatitis, psoriasis, sunburn, or conjunctivitis.
 26. A method oftreating the common cold or respiratory viral infection caused by humanrhinovirus (HRV), other enteroviruses, coronavirus, influenza virus,parainfluenza virus, respiratory syncytial virus, or adenovirus in ahuman in need thereof which method comprises administering to said humanan effective amount of a compound according to claim
 1. 27. The methodaccording to claim 26 wherein the respiratory viral infectionexacerbates asthma, exacerbates chronic bronchitis, exacerbates chronicobstructive pulmonary disease, exacerbates otitis media, exacerbatessinusitis, or wherein the respiratory viral infection is associated witha secondary bacterial infection, otitis media, sinusitis, or pneumonia.28. A compound of the formula:

wherein R₁ is an optionally substituted aryl or an optionallysubstituted heteroaryl ring; X is R₂, OR₂, S(O)_(m)R₂,(CH₂)_(n)N(R₁₀)S(O)_(m)R₂, (CH₂)_(n)N(R₁₀)C(O)R₂, (CH₂)_(n)NR₄R₁₄,NR₂(CH₂)_(n)NR₄R₁₄, O(CH₂)_(n)NR₄R₁₄, S(CH₂)_(n)NR₄R₁₄, (CH₂)_(n)J,NR₂(CH₂)_(n)J, O(CH₂)_(n)J, S(CH₂)_(n)J, or (CH₂)_(n)N(R₂)₂; J is anoptionally substituted heteroaryl ring; n is 0 or an integer having avalue of 1 to 10; m is 0 or an integer having a value of 1 or 2; q is 0or an integer having a value of 1 to 10; R₂ is hydrogen, C₁₋₁₀ alkyl,aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, which moietiesare all optionally substituted, or R₂ is the moietyX₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or C(A₁)(A₂)(A₃); X₁ is N(R₁₀), O,S(O)_(m), or CR₁₀R₂₀; X₂ is independently hydrogen, halogen or C₁₋₄alkyl; A₁ is an optionally substituted C₁₋₁₀ alkyl; A₂ is an optionallysubstituted C₁₋₁₀ alkyl; A₃ is hydrogen or is an optionally substitutedC₁₋₁₀ alkyl; G₂ is C—X₂; R₃ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl,C₃₋₇ cycloalkyl C₁₋₄alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl,heteroarylC₁₋₁₀ alkyl, heterocyclic, or a heterocyclylC₁₋₁₀ alkylmoiety, which moieties are optionally substituted; provided that when X₂is hydrogen, R₁ is an optionally substituted phenyl or a methylsubstituted imidazol-1-yl, X is R₂ and R₂ is hydrogen, then R₃ is otherthan hydrogen or methyl; R₄ and R₁₄ are each independently selected fromhydrogen, optionally substituted C₁₋₄ alkyl, optionally substitutedaryl, or optionally substituted aryl-C₁₋₄ alkyl, arylC₁₋₁₀ alkyl,heteroaryl or heteroarylC₁₋₁₀ alkyl, wherein each of these moieties maybe optionally substituted; R₁₀ and R₂₀ are independently selected fromhydrogen or C₁₋₄alkyl; or a pharmaceutically acceptable salt thereof.29. The compound according to claim 28 which is Formula (III), or apharmaceutically acceptable salt thereof.
 30. The compound according toclaim 28 which is Formula (IIIa), or a pharmaceutically acceptable saltthereof.
 31. The compound according to claim 28 wherein R₁ is anoptionally substituted phenyl or naphthyl.
 32. The compound according toclaim 31 wherein the phenyl is substituted one or more timesindependently by halogen, alkyl, hydroxy, alkoxy, amino, orhalosubstituted alkyl.
 33. The compound according to claim 32 whereinthe substituents are independently fluorine, C₁₋₄ alkyl, or CF₃.
 34. Thecompound according to claim 32 wherein the phenyl ring is substituted inthe 2, 4, or 6-position, di-substituted in the 2, 4-position, ortri-substituted in the 2,4,6-position.
 35. The compound according toclaim 28 wherein X is OR₂, or S(O)mR₂.
 36. The compound according toclaim 28 wherein X is (CH₂)_(n)NR₄R₁₄, or (CH₂)_(n)N(R₂)₂.
 37. Thecompound according to claim 28 wherein X is R₂ or (CH₂)nN(R₁₀)S(O)mR₂,or (CH₂)nN(R₁₀)C(O)R₂.
 38. The compound according to claim 28 whereinR₂, other then hydrogen, is optionally substituted independently one ormore times with C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl,C₅₋₇cycloalkenyl, C₅₋₇ cycloalkenyl C₁₋₁₀ alkyl, halogen, —C(O), cyano,nitro, (CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH, (CR₁₀R₂₀)_(n)S(O)_(m)R₇,(CR₁₀R₂₀)_(n)NR₁₀S(O)₂R₇, (CR₁₀R₂₀)_(n)NR₄R₁₄, (CR₁₀R₂₀)_(n)CN,(CR₁₀R₂₀)_(n)S(O)₂NR₄R₁₄, (CR₁₀R₂₀)_(n)C(Z)R₆, (CR₁₀R₂₀)_(n)OC(Z)R₆,(CR₁₀R₂₀)_(n)C(Z)OR₆, (CR₁₀R₂₀)_(n)C(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)R₆,(CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₀)NR₄R₁₄, (CR₁₀R₂₀)_(n)C(═NOR₆)NR₄R₁₄,(CR₁₀R₂₀)_(n)OC(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₄R₁₄, or(CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₇; and wherein R₆ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, heterocyclyl, heterocyclyl C₁₋₁₀alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl or heteroarylC₁₋₁₀ alkyl, wherein these moieties,excluding hydrogen, are optionally substituted; R₇ is C₁₋₆alkyl, aryl,arylC₁₋₆alkyl, heterocyclic, heterocyclylC₁₋₆ alkyl, heteroaryl, orheteroarylC₁₋₆alkyl; and wherein each of these moieties are optionallysubstituted.
 39. The compound according to claim 36 wherein R₂ is anoptionally substituted alkyl.
 40. The compound according to claim 39wherein the alkyl is an optionally substituted by (CR₁₀R₂₀)_(n)C(Z)OR₆,(CR₁₀R₂₀)_(n)OR₆, or (CR₁₀R₂₀)_(n)NR₄R₁₄; and wherein R₆ is hydrogen,C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, heterocyclyl C₁₋₁₀alkyl,aryl, arylC₁₋₁₀ alkyl, heteroaryl or heteroarylC₁₋₁₀ alkyl, whereinthese moieties, excluding hydrogen, are optionally substituted;
 41. Thecompound according to claim 28 wherein R₂ is theX₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or C(A₁)(A₂)(A₃).
 42. The compoundaccording to claim 41 wherein X₁ is oxygen or N(R₁₀).
 43. The compoundaccording to claim 41 wherein at least one of A₁, A₂ or A₃ issubstituted by (CR₁₀R₂₀)_(n)OR₆; and wherein R₆ is hydrogen, C₁₋₁₀alkyl, C₃₋₇ cycloalkyl, heterocyclyl, heterocyclyl C₁₋₁₀alkyl, aryl,arylC₁₋₁₀ alkyl, heteroaryl or heteroarylC₁₋₁₀ alkyl, wherein thesemoieties, excluding hydrogen, are optionally substituted;
 44. Thecompound according to claim 43 wherein q is 1 or
 2. 45. The compoundaccording to any claim 28 wherein R₃ is an optionally substituted C₁₋₁₀alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylalkyl, aryl, or aryl C₁₋₁₀ alkyl.46. The compound according to claim 45 wherein R₃ is optionallysubstituted one or more times independently with C₁₋₁₀ alkyl,halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀ alkyl, C₅₋₇cycloalkenyl,C₅₋₇cycloalkenylC₁₋₁₀ alkyl, halogen, cyano, nitro, (CR₁₀R₂₀)_(n)OR₆,(CR₁₀R₂₀)_(n)SH, (CR₁₀R₂₀)_(n)S(O)_(m)R₇, (CR₁₀R₂₀)_(n)NR₁₀S(O)₂R₇,(CR₁₀R₂₀)_(n)NR₄R₁₄, (CR₁₀R₂₀₎ _(n)CN, (CR₁₀R₂₀)_(n)S(O)₂NR₄R₁₄,(CR₁₀R₂₀)_(n)C(Z)R₆, (CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆,(CR₁₀R₂₀)_(n)C(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)R₆,(CR₁₀R₂₀)_(n)NR₁C(═NR₁₀)NR₄R₁₄, (CR₁₀R₂₀)_(n)OC(Z)NR₄R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₄R₁₄, or (CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₇; and wherein R₆is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, heterocyclylC₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl or heteroarylC₁₋₁₀ alkyl,wherein these moieties, excluding hydrogen, are optionally substituted;R₇ is C₁₋₆alkyl, aryl, arylC₁₋₆alkyl, heterocyclic, heterocyclylC₁₋₁₆alkyl, heteroaryl, or heteroarylC₁₋₆alkyl; and wherein each of thesemoieties are optionally substituted.
 47. The compound according to claim46 wherein the optional substituent is halogen, C₁₋₁₀ alkyl, hydroxy,alkoxy, amino, or halosubstituted C₁₋₁₀alkyl.
 48. The compound accordingto claim 28 wherein X₂ is hydrogen.
 49. The compound according to claim28, which is:7-Bromo-1,5-bis(2-chlorophenyl)-3,4-dihydro[1,6]naphthyridin-2(1H)-one;7-Bromo-1,5-bis(2-chlorophenyl)[1,6]naphthyridin-2(1H)-one;1,5-Bis(2-Chlorophenyl)-7-[(2-hydroxy-1-(hydroxymethyl)ethyl]-amino]-[1,6]naphthyridin-2(1H)-one;N-[2-[[1,5-bis(2-Chlorophenyl)-2-oxo-1,2-dihydro[1,6]naphthyridin-7-yl]amino]ethyl]acetamide;1,5-Bis(2-Chlorophenyl)-7-[(1H-imidazol-2-ylmethyl)amino][1,6]naphthyridin-2(1H)-one;1,5-Bis(2-Chlorophenyl)-7-[[2-(Isopropylamino)ethyl]amino][1,6]naphthyridin-2(1H)-one;1,5-Bis(2-Chlorophenyl)-7-amino-[1,6]naphthyridin-2(1H)-one;1,5-Bis(2-Chlorophenyl)-7-chloro-[1,6]naphthyridin-2(1H)-one; or apharmaceutically acceptable salt thereof.
 50. A pharmaceuticalcomposition comprising an effective amount of a compound according toclaim 28 and a pharmaceutically acceptable carrier or diluent.
 51. Amethod of treating a CSBP/RK/p38 mediated disease in a mammal in needthereof comprising administering to said mammal an effective amount of acompound according to claim
 28. 52. The method according to claim 51wherein the CSBP/RK/p38 kinase mediated disease is psoriatic arthritis,Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acutesynovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis,gouty arthritis and other arthritic condition, sepsis, septic shock,endotoxic shock, gram negative sepsis, toxic shock syndrome, cerebralmalaria, meningitis, ischemic and hemorrhagic stroke, neurotrauma/closedhead injury, asthma, adult respiratory distress syndrome, chronicpulmonary inflammatory disease, chronic obstructive pulmonary disease,silicosis, pulmonary sarcososis, bone resorption disease, osteoporosis,restenosis, cardiac and brain and renal reperfusion injury, congestiveheart failure, coronary arterial bypass grafting (CABG) surgery,thrombosis, glomerularnephritis, chronic renal failure, diabetes,diabetic retinopathy, macular degeneration, graft vs. host reaction,allograft rejection, inflammatory bowel disease, Crohn's disease,ulcerative colitis, neurodegenrative disease, muscle degeneration,diabetic retinopathy, macular degeneration, tumor growth and metastasis,angiogenic disease, influenza induced pneumonia, eczema, contactdermatitis, psoriasis, sunburn, or conjunctivitis.
 53. A method oftreating the common cold or respiratory viral infection caused by humanrhinovirus (HRV), other enteroviruses, coronavirus, influenza virus,parainfluenza virus, respiratory syncytial virus, or adenovirus in ahuman in need thereof which method comprises administering to said humanan effective amount of a compound according to claim
 28. 54. The methodaccording to claim 53 wherein the respiratory viral infectionexacerbates asthma, exacerbates chronic bronchitis, exacerbates chronicobstructive pulmonary disease, exacerbates otitis media, exacerbatessinusitis, or wherein the respiratory viral infection is associated witha secondary bacterial infection, otitis media, sinusitis, or pneumonia.55. A compound of the formula:

wherein R₁ is an optionally substituted aryl or an optionallysubstituted heteroaryl ring; X is R₂, OR₂, S(O)_(m)R₂,(CH₂)_(n)N(R₁₀)S(O)_(m)R₂, (CH₂)_(n)N(R₁₀)C(O)R₂, (CH₂)_(n)NR₄R₁₄,NR₂(CH₂)_(n)NR₄R₁₄, O(CH₂)_(n)NR₄R₁₄, S(CH₂)_(n)NR₄R₁₄, (CH₂)_(n)J,NR₂(CH₂)_(n)J, O(CH₂)_(n)J, S(CH₂)_(n)J, or (CH₂)_(n)N(R₂)₂; J is anoptionally substituted heteroaryl ring; n is 0 or an integer having avalue of 1 to 10; m is 0 or an integer having a value of 1 or 2; q is 0or an integer having a value of 1 to 10; R₂ is hydrogen, C₁₋₁₀ alkyl,aryl, arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, which moietiesare all optionally substituted, or R₂ is the moietyX₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or C(A₁)(A₂)(A₃); X₁ is N(R₁₀), O,S(O)_(m), or CR₁₀R₂₀; X₂ is independently hydrogen, halogen or C₁₋₄alkyl; A₁ is an optionally substituted C₁₋₁₀ alkyl; A₂ is an optionallysubstituted C₁₋₁₀ alkyl; A₃ is hydrogen or is an optionally substitutedC₁₋₁₀ alkyl; G₁ and G₂ are independently C—X₂; R₃ is a hydrogen, C₁₋₁₀alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl, aryl, arylC₁₋₁₀ alkyl,heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or a heterocyclylC₁₋₁₀alkyl moiety, which moieties are optionally substituted; R₄ and R₁₄ areeach independently selected from hydrogen, optionally substituted C₁₋₄alkyl, optionally substituted aryl, or optionally substituted aryl-C₁₋₁₄alkyl, arylC₁₋₁₀ alkyl, heteroaryl or heteroarylC₁₋₁₀ alkyl, whereineach of these moieties may be optionally substituted; R₁₀ and R₂₀ areindependently selected from hydrogen or C₁₋₄alkyl; provided that when R₁is phenyl, R₃ is methoxy substituted phenyl, X is (CH₂)_(n)NR₄R₁₄, and nis 0, then R₄ and R₁₄ are other than both methyl; or when R₁ is a2-chlorophenyl, or a 2-Cl,4-F-phenyl, and R₃ is a 2,6-dichlorophenyl,and X is OR₂, then R₂ is other than methyl; or a pharmaceuticallyacceptable salt thereof.
 56. The compound according to claim 55 which isFormula (IV) or a pharmaceutically acceptable salt thereof.
 57. Thecompound according to claim 55 which is Formula (IVa) or apharmaceutically acceptable salt thereof.
 58. The compound according toclaim 55 wherein R₁ is an optionally substituted phenyl or naphthyl. 59.The compound according to claim 58 wherein the phenyl is substituted oneor more times independently by halogen, alkyl, hydroxy, alkoxy, amino,or halosubstituted alkyl.
 60. The compound according to claim 59 whereinthe substituents are independently fluorine, C₁₋₄ alkyl, or CF₃.
 61. Thecompound according to claim 59 wherein the phenyl ring is substituted inthe 2, 4, or 6-position, di-substituted in the 2,4-position, ortri-substituted in the 2,4,6-position.
 62. The compound according toclaim 55 wherein X is OR₂, or S(O)mR₂.
 63. The compound according toclaim 55 wherein X is (CH₂)_(n)NR₄R₁₄, or (CH₂)_(n)N(R₂)₂.
 64. Thecompound according to claim 55 wherein X is R₂ or (CH₂)nN(R₁₀)S(O)mR₂,or (CH₂)nN(R₁₀)C(O)R₂.
 65. The compound according to claim 55 whereinR₂, other then hydrogen, is optionally substituted independently one ormore times with C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkylC₁₋₁₀alkyl,C₅₋₇cycloalkenyl, C₅₋₇ cycloalkenyl C₁₋₁₀ alkyl, halogen, —C(O), cyano,nitro, (CR₁₀R₂₀)_(n)OR₆, (CR₁₀R₂₀)_(n)SH, (CR₁₀R₂₀)_(n)S(O)_(m)R₇,(CR₁₀R₂₀)_(n)NR₁₀S(O)₂R₇, (CR₁₀R₂₀)_(n)NR₄R₁₄, (CR₁₀R₂₀)_(n)CN,(CR₁₀R₂₀)_(n)S(O)₂NR₄R₁₄, (CR₁₀R₂₀)_(n)C(Z)R₆, (CR₁₀R₂₀)_(n)OC(Z)R₆,(CR₁₀R₂₀)_(n)C(Z)OR₆, (CR₁₀R₂₀)_(n)C(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)R₆,(CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₀)N₄R₁₄, (CR₁₀R₂₀)_(n)C(═NOR₆)NR₄R₁₄,(CR₁₀R₂₀)_(n)OC(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₄R₁₄, or(CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₇; and wherein R₆ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇cycloalkyl, heterocyclyl, heterocyclyl C₁₋₁₀ alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl or heteroarylC₁₋₁₀ alkyl, wherein these moieties,excluding hydrogen, are optionally substituted; R₇ is C₆alkyl, aryl,arylC₁₋₆alkyl, heterocyclic, heterocyclylC₁₋₆ alkyl, heteroaryl, orheteroarylC₁₋₆alkyl; and wherein each of these moieties are optionallysubstituted.
 66. The compound according to claim 63 wherein R₂ is anoptionally substituted alkyl.
 67. The compound according to claim 66wherein the alkyl is an optionally substituted by (CR₁₀R₂₀)_(n)C(Z)OR₆,(CR₁₀R₂₀)_(n)OR₆, or (CR₁₀R₂₀)_(n)NR₄R₁₄.
 68. The compound according toclaim 55 wherein R₂ is the X₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), orC(A₁)(A₂)(A₃).
 69. The compound according to claim 68 wherein X₁ isoxygen or N(R10).
 70. The compound according to claim 68 wherein atleast one of A₁, A₂ or A₃ is substituted by (CR₁₀R₂₀)OR₆ and wherein R₆is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, heterocyclylC₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl or heteroarylC₁₋₁₀ alkyl,wherein these moieties, excluding hydrogen, are optionally substituted.71. The compound according to claim 68 wherein q is 1 or
 2. 72. Thecompound according to claim 55 wherein R₃ is an optionally substitutedC₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylalkyl, aryl, or aryl C₁₋₁₀alkyl.
 73. The compound according to claim 72 wherein R₃ is optionallysubstituted one or more times independently with C₁₋₁₀ alkyl,halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkyC₁₋₁₀ alkyl, C₅₋₇cycloalkenyl,C₅₋₇cycloalkenylC₁₋₁₀ alkyl, halogen, cyano, nitro, (CR₁₀R₂₀)_(n)OR₆,(CR₁₀R₂₀)_(n)SH, (CR₁₀R₂₀)_(n)S(O)_(m)R₇, (CR₁₀R₂₀)_(n)NR₁₀S(O)₂R₇,(CR₁₀R₂₀)_(n)NR₄R₁₄, (CR₁₀R₂₀)_(n)CN, (CR₁₀R₂₀)_(n)S(O)₂NR₄R₁₄,(CR₁₀R₂₀)_(n)C(Z)R₆, (CR₁₀R₂₀)_(n)OC(Z)R₆, (CR₁₀R₂₀)_(n)C(Z)OR₆,(CR₁₀R₂₀)_(n)C(Z)NR₄R₁₄, (CR₁₀R₂₀)_(n)NR₁₀C(Z)R₆,(CR₁₀R₂₀)_(n)NR₁₀C(═NR₁₀)NR₄R₁₄, (CR₁₀R₂₀)_(n)OC(Z)NR₄R₁₄,(CR₁₀R₂₀)_(n)NR₁₀C(Z)NR₄R₁₄, or (CR₁₀R₂₀)_(n)NR₁₀C(Z)OR₇; and wherein R₆is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, heterocyclylC₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl or heteroarylC₁₋₁₀ alkyl,wherein these moieties, excluding hydrogen, are optionally substituted;R₇ is C₁₋₆alkyl, aryl, arylC₁₋₆alkyl, heterocyclic, heterocyclylC₁₋₆alkyl, heteroaryl, or heteroarylC₁₋₆alkyl; and wherein each of thesemoieties are optionally substituted.
 74. The compound according to claim73 wherein the optional substituent is halogen, alkyl, hydroxy, alkoxy,amino, or halosubstituted alkyl.
 75. The compound according to claim 55wherein X₂ is hydrogen.
 76. The compound according to claim 55 which is:5-(2-fluorophenyl)-1-(4-flourophenyl)-2(1H)-quinolinone;5-(4-fluorophenyl)-1-(4-fluorophenyl)-2(1H)-quinolinone;5-(2,4-difluorophenyl)-1-(4-fluorophenyl)-2(1H)-quinolinone;5-(4-methylphenyl)-1-(4-fluorophenyl)-2(1H)-quinolinone;1,5-bis(2-chlorophenyl)-7-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-2(1H)-quinolinone;1,5-Bis(2-chlorophenyl)-7-{[2-(isopropylamino)ethyl]amino}-2(1H)-quinolinone;6-bromo-1,5-bis(2-chlorophenyl)-7-(methyloxy)-2(1H)-quinolinone; or apharmaceutically acceptable salt thereof.
 77. A pharmaceuticalcomposition comprising an effective amount of a compound according toclaim 55 and a pharmaceutically acceptable carrier or diluent.
 78. Amethod of treating a CSBP/RK/p38 mediated disease in a mammal in needthereof comprising administering to said mammal an effective amount of acompound according to claim
 55. 79. The method according to claim 78wherein the CSBP/RK/p38 kinase mediated disease is psoriatic arthritis,Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acutesynovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis,gouty arthritis and other arthritic condition, sepsis, septic shock,endotoxic shock, gram negative sepsis, toxic shock syndrome, cerebralmalaria, meningitis, ischemic and hemorrhagic stroke, neurotrauma/closedhead injury, asthma, adult respiratory distress syndrome, chronicpulmonary inflammatory disease, chronic obstructive pulmonary disease,silicosis, pulmonary sarcososis, bone resorption disease, osteoporosis,restenosis, cardiac and brain and renal reperfusion injury, congestiveheart failure, coronary arterial bypass grafting (CABG) surgery,thrombosis, glomerularnephritis, chronic renal failure, diabetes,diabetic retinopathy, macular degeneration, graft vs. host reaction,allograft rejection, inflammatory bowel disease, Crohn's disease,ulcerative colitis, neurodegenrative disease, muscle degeneration,diabetic retinopathy, macular degeneration, tumor growth and metastasis,angiogenic disease, influenza induced pneumonia, eczema, contactdermatitis, psoriasis, sunburn, or conjunctivitis.
 80. A method oftreating the common cold or respiratory viral infection caused by humanrhinovirus (HRV), other enteroviruses, coronavirus, influenza virus,parainfluenza virus, respiratory syncytial virus, or adenovirus in ahuman in need thereof which method comprises administering to said humanan effective amount of a compound according to claim
 55. 81. The methodaccording to claim 80 wherein the respiratory viral infectionexacerbates asthma, exacerbates chronic bronchitis, exacerbates chronicobstructive pulmonary disease, exacerbates otitis media, exacerbatessinusitis, or wherein the respiratory viral infection is associated witha secondary bacterial infection, otitis media, sinusitis, or pneumonia.82. A method of treating a CSBP/RK/p38 mediated disease in a mammal inneed thereof comprising administering to said mammal an effective amountof a compound of the formula

wherein R₁ is an optionally substituted aryl or an optionallysubstituted heteroaryl ring; X is halogen, R₂, OR₂, S(O)_(m)R₂,(CH₂)_(n)N(R₁₀)S(O)_(m)R₂, (CH₂)_(n)N(R₁₀)C(O)R₂, (CH₂)_(n)NR₄R₁₄,NR₂(CH₂)_(n)NR4R14, O(CH₂)_(n)NR4R14, S(CH₂)_(n)NR4R14, (CH₂)_(n)J,NR2(CH2)nJ, O(CH2)nJ, S(CH2)nJ, or (CH₂)_(n)N(R₂)₂; J is an optionallysubstituted heteroaryl ring; n is 0 or an integer having a value of 1 to10; m is 0 or an integer having a value of 1 or 2; q is 0 or an integerhaving a value of 1 to 10; R₂ is hydrogen, C₁₋₁₀ alkyl, aryl, arylC₁₋₁₀alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, which moieties are alloptionally substituted, or R₂ is the moietyX₁(CR₁₀R₂₀)_(q)C(A₁)(A₂)(A₃), or C(A₁)(A₂)(A₃); X₁ is N(R₁₀), O,S(O)_(m), or CR₁₀R₂₀; X₂ is independently hydrogen, halogen or C₁₋₄alkyl; A₁ is an optionally substituted C₁₋₁₀ alkyl; A₂ is an optionallysubstituted C₁₋₁₀ alkyl; A₃ is hydrogen or is an optionally substitutedC₁₋₁₀ alkyl; G₁ and G₂ are independently selected from is N, or C—X₂,provided that G₁ and G₂ are not both nitrogen; R₃ is an hydrogen, C₁₋₁₀alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkylC₁₋₄alkyl, aryl, arylC₁₋₁₀ alkyl,heteroaryl, heteroarylC₁₋₁₀ alkyl, heterocyclic, or a heterocyclylC₁₋₁₀alkyl moiety, which moieties are optionally substituted; R₄ and R₁₄ areeach independently selected from hydrogen, optionally substituted C₁₋₄alkyl, optionally substituted aryl, or optionally substituted aryl-C₁₋₄alkyl, arylC₁₋₁₀ alkyl, heteroaryl or heteroarylC₁₋₁₀ alkyl, whereineach of these moieties may be optionally substituted; R₆ is hydrogen,C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, heterocyclyl C₁₋₁₀alkylaryl, arylC₁₋₁₀ alkyl, heteroaryl or heteroarylC₁₋₁₀ alkyl, whereinthese moieties, excluding hydrogen, are optionally substituted. R₉ ishydrogen, C(Z)R₆ or optionally substituted C₁₋₁₀ alkyl, optionallysubstituted aryl or optionally substituted aryl-C₁₋₄ alkyl; R₁₀ and R₂₀are independently selected from hydrogen or C₁₋₄alkyl; or apharmaceutically acceptable salt thereof.
 83. The method according toclaim 82 wherein the compound is:1-methyl-5-phenyl-1H-[1,6]naphthyridin-2-one; or5-phenyl-1H-[1,6]naphthyridin-2-one; or a pharmaceutically acceptablesalt thereof.
 84. The compound which is:1,5-bis(4-fluorophenyl)[1,8]naphthyridin-2(1H)-one;5-(2,4-difluorophenyl)-1-(4-fluorophenyl)[1,8]naphthyridin-2(1H)-one;7-Bromo-1,5-bis(2-chlorophenyl)-3,4-dihydro[1,6]naphthyridin-2(1H)-one;7-Bromo-1,5-bis(2-chlorophenyl) [1,6]naphthyridin-2(1H)-one;1,5-Bis(2-Chlorophenyl)-7-[(2-hydroxy-1-(hydroxymethyl)ethyl]-amino]-[1,6]naphthyridin-2(1H)-one;N-[2-[[1,5-bis(2-Chlorophenyl)-2-oxo-1,2-dihydro[1,6]naphthyridin-7-yl]amino]ethyl]acetamide;1,5-Bis(2-Chlorophenyl)-7-[(1H-imidazol-2-ylmethyl)amino][1,6]naphthyridin-2(1H)-one;1,5-Bis(2-Chlorophenyl)-7-[[2-(Isopropylamino)ethyl]amino][1,6]naphthyridin-2(1H)-one;1,5-Bis(2-Chlorophenyl)-7-amino-[1,6]naphthyridin-2(1H)-one;1,5-Bis(2-Chlorophenyl)-7-chloro-[1,6]naphthyridin-2(1H)-one;5-(2-fluorophenyl)-1-(4-flourophenyl)-2(1H)-quinolinone;5-(4-fluorophenyl)-1-(4-fluorophenyl)-2(1H)-quinolinone;5-(2,4-difluorophenyl)-1-(4-fluorophenyl)-2(1H)-quinolinone;5-(4-methylphenyl)-1-(4-fluorophenyl)-2(1H)-quinolinone;1,5-bis(2-chlorophenyl)-7-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-2(1H)-quinolinone;1,5-Bis(2-chlorophenyl)-7-{[2-(isopropylamino)ethyl]amino}-2(1H)-quinolinone;6-bromo-1,5-bis(2-chlorophenyl)-7-(methyloxy)-2(1H)-quinolinone;1-Benzyl-5-phenyl-1H-[1,6]naphthyridin-2-one; or1,5-Diphenyl-1H-[1,6]naphthyridin-2-one; or a pharmaceuticallyacceptable salt thereof.
 85. A pharmaceutical composition comprising aneffective amount of a compound according to claim 84 and apharmaceutically acceptable carrier or diluent.